Ca2 + signaling and emesis: Recent progress and new perspectives

AUTNEU-01854; No of Pages 10 Autonomic Neuroscience: Basic and Clinical xxx (2016) xxx–xxx

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Review

Ca2 + signaling and emesis: Recent progress and new perspectives Weixia Zhong, Andrew J. Picca, Albert S. Lee, Nissar A. Darmani ⁎ Department of Basic Medical Sciences, College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA 91766, USA

a r t i c l e

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Article history: Received 21 April 2016 Received in revised form 21 July 2016 Accepted 22 July 2016 Available online xxxx Keywords: Cancer Cisplatin Vomiting Emesis Antiemesis Ca2+ L-type Ca2+ channel Palonosetron Netupitant CB1 receptor

a b s t r a c t Cisplatin-like chemotherapeutics cause vomiting via calcium (Ca2+)-dependent release of multiple neurotransmitters (dopamine, serotonin, substance P, etc.) from the gastrointestinal enterochromaffin cells and/or the brainstem. Intracellular Ca2+ signaling is triggered by activation of diverse emetic receptors (including tachykininergic NK1, serotonergic 5-HT3, dopaminergic D2, cholinergic M1, or histaminergic H1), whose activation in vomit-competent species can evoke emesis. Other emetogens such as cisplatin, rotavirus NSP4 protein and bacterial toxins can also induce intracellular Ca2+ elevation. Netupitant is a highly selective neurokinin NK1 receptor (NK1R) antagonist and palonosetron is a selective second-generation serotonin 5-HT3 receptor (5HT3R) antagonist with a distinct pharmacological profile. An oral fixed combination of netupitant/palonosetron (NEPA; Akynzeo(®)) with N 85% antiemetic efficacy is available for use in the prevention of acute and delayed chemotherapy-induced nausea and vomiting (CINV). Cannabinoid CB1 receptor agonists possess broadspectrum antiemetic activity since they prevent vomiting caused by a variety of emetic stimuli including the chemotherapeutic agent cisplatin, 5-HT3R agonists, and D2R agonists. Our findings demonstrate that application of the L-type Ca2+ channel (LTCC) agonist FPL 64176 and the intracellular Ca2+ mobilizing agent thapsigargin (a sarco/endoplasmic reticulum Ca2+-ATPase inhibitor) cause vomiting in the least shrew. On the other hand, blockade of LTCCs by corresponding antagonists (nifedipine or amlodipine) not only provide broad-spectrum antiemetic efficacy against diverse agents that specifically activate emetogenic receptors such as 5-HT3, NK1, D2, and M1 receptors, but can also potentiate the antiemetic efficacy of palonosetron against the non-specific emetogen, cisplatin. In this review, we will provide an overview of Ca2+ involvement in the emetic process; discuss the relationship between Ca2+ signaling and the prevailing therapeutics in control of vomiting; highlight the evidence for Ca2+-signaling blockers/inhibitors in suppressing emetic behavior in the least shrew model of emesis as well as in the clinical setting; and also draw attention to the clinical benefits of Ca2+-signaling blockers/inhibitors in the treatment of nausea and vomiting. © 2016 Published by Elsevier B.V.

Contents 1. 2.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Emerging roles of Ca2 + in emesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Emetic receptor stimulation increases intracellular Ca2 + concentration . . . . . . . . . . . 2.2. Emetic potential of Ca2 + channel activators. . . . . . . . . . . . . . . . . . . . . . . . 3. Ca2 + intervention: mechanisms and potential therapeutic approaches . . . . . . . . . . . . . . . 3.1. Receptor antagonist antiemetic regimens such as NEPA . . . . . . . . . . . . . . . . . . 3.2. Cannabinoid CB1 receptor agonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. Perspective in developing new antiemetic candidates . . . . . . . . . . . . . . . . . . . . . . 4.1. Antiemetic efficacy of LTCC blockers in the least shrew model of emesis . . . . . . . . . . . 4.2. Potentiation of anti-emetic efficacy of 5-HT3R antagonists when combined with LTCC blockers 4.3. Clinical use of L-type Ca2 + channel blockers as anti-nausea/anti-emetic medication . . . . . 4.4. Internal Ca2 + release channels: Possible targets in preventing emesis . . . . . . . . . . . . 5. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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⁎ Corresponding author at: Department of Basic Medical Sciences, College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, 309 East Second Street, Pomona, CA 91766, USA. E-mail address: [email protected] (N.A. Darmani).

http://dx.doi.org/10.1016/j.autneu.2016.07.006 1566-0702/© 2016 Published by Elsevier B.V.

Please cite this article as: Zhong, W., et al., Ca2+ signaling and emesis: Recent progress and new perspectives, Auton. Neurosci. (2016), http:// dx.doi.org/10.1016/j.autneu.2016.07.006

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1. Introduction

signaling in emesis generation and the corresponding development of potential novel antiemetic medications, as briefly shown in Fig. 1.

Acute (≤ 24 h) and delayed (N24 h) phases of chemotherapyinduced nausea and vomiting (CINV) cause distressing effects which affect the well-being and quality of life of cancer patients receiving chemotherapy, especially cisplatin (Kottschade et al., 2016). Major neurotransmitter mechanisms underlying CINV have been subject of considerable research over the past 25 years. Chemotherapeutics such as cisplatin induce vomiting via release of a wide variety of emetic neurotransmitters/mediators (such as dopamine, serotonin (5-HT), substance P (SP), prostaglandins and leukotrienes) in both the gastrointestinal tract (GIT) and the emetic loci of the dorsal vagal complex (DVC) in the brainstem including the nucleus tractus solitarius (NTS), the dorsal motor nucleus of the vagus (DMNX) and the area postrema (AP) (Darmani and Ray, 2009; Guttuso, 2014; Ray et al., 2009a). The AP and the NTS contain large numbers of fenestrated capillaries which lack blood brain barrier and permit neurons in both areas access to circulating factors including emetogens (Rogers et al., 2006a). The NTS is a key site for integrating diverse emesis-related information from the brain as well as the GIT conveyed by the vagal afferents which terminate preferentially in the NTS and to a lesser extent in the DMNX. The DMNX sends emetic signals via efferents to the GIT and modulates vomiting behaviors (Babic and Browning, 2014; Darmani and Ray, 2009; Rogers et al., 2006a; Rojas and Slusher, 2015). Ca2 + is not only one of the most universal and versatile signaling molecules, it is also an extremely important factor in both the physiology and pathology of living organisms. At rest, diverse cells have strict and well-regulated mechanisms to maintain low nM cytosolic Ca2 + levels (Seaton et al., 2011). Cytoplasmic Ca2+ concentration is a dominant factor in determining the amount of transmitter released from nerve terminals (Katz and Miledi, 1967). Thus, Ca2+ mobilization can be an important aspect of vomit induction since it is involved in both triggering the quantity of neurotransmitter released coupled with receptor activation, as well as post-receptor excitation-transcription coupling mechanisms (Zuccotti et al., 2011). Studies using Ca2+ imaging performed in vitro in the brainstem slice preparation suggest that emetic agents evoke direct excitatory effects on cytosolic Ca2 + signals in vagal afferent terminals in the NTS which potentiate local neurotransmitter release (Rogers et al., 2006a, 2006b; Rogers and Hermann, 2012). Therefore, chemotherapeutics including cisplatin seem to activate emetic circuits through a number of neurotransmitters released Ca2 +-dependently in specific vomit-associated neuroanatomical structures. In both the periphery and the brainstem, emetic neurotransmitters/mediators—such as acetylcholine, dopamine, 5-HT, SP, prostaglandins, leukotrienes, and/or histamine—may act independently or in combination to evoke vomiting (Darmani et al., 2009). In this review, we focus on the current evidence supporting the significance of Ca2+

2. Emerging roles of Ca2+ in emesis 2.1. Emetic receptor stimulation increases intracellular Ca2+ concentration Excitatory receptor activation by corresponding agonists can increase cytosolic Ca2+ levels via both mobilization of intracellular Ca2+ stores (e.g. endoplasmic reticulum = ER) and influx from extracellular fluid (Suzuki et al., 2010). The evoked cytoplasmic Ca2+ increase may result from direct activation of ion channels, or indirectly via signal transduction pathways following G protein-coupled receptor activation. The neurokinin NK1 receptor (NK1R) is a member of the tachykinin family of receptors which is G-protein coupled. NK1R stimulation by substance P or corresponding selective agonists such as GR73632, can increase cytosolic Ca2+ concentration. In fact GR73632-induced activation of NK1Rs can evoke intracellular Ca2+ release from the sarco/endoplasmic reticulum (SER) stores via Gαq-mediated phospholipase C pathway, which subsequently evokes extracellular Ca2+ influx through L-type Ca2 + channels (LTCCs) (Lin et al., 2005; Miyano et al., 2010; Suzuki et al., 2010). The serotonergic 5-HT3 receptor (5-HT3R) is a Ca2 +-permeable ligand-gated ion channel (Hargreaves et al., 1996). Cell line studies have demonstrated that activation of 5-HT3Rs by serotonin or its analogs can evoke extracellular Ca2+ influx into cells in a manner sensitive to both 5-HT3R antagonists (tropisetron, MDL7222, metoclopramide) and LTCC blockers (verapamil, nimodipine, nitrendipine) (Hargreaves et al., 1996; Homma et al., 2006; Hutchinson et al., 2015; Ronde and Nichols, 1997; Takenouchi and Munekata, 1998). These studies suggest that both L-type- and 5-HT3receptor Ca2 +-permeable ion channels are involved in extracellular Ca2+ influx evoked by 5-HT3R agonists. Moreover, 5-HT3R activation indirectly causes release of Ca2+ from ryanodine-sensitive intracellular calcium stores subsequent to the evoked extracellular Ca2 + influx which greatly amplifies the cytoplasmic concentration of Ca2+ (Ronde and Nichols, 1997). In fact our findings from behavioral studies (Zhong et al., 2014b) further support the notion of Ca2 +-induced Ca2+ release following 5-HT3R stimulation, which will be discussed in more detail in Section 4.4. Other emetogens such as agonists of dopamine D2 (Aman et al., 2007; Wu et al., 2006)-, cholinergic M1 (Oliveira and Correia-de-Sa, 2005; Sculptoreano et al., 2001)-, histaminergic H1 (Barajas et al., 2008; Yoshimoto et al., 1998)- and opiate μ (Ono et al., 2002; Smart et al., 1997)-receptors, as well as cisplatin (Splettstoesser et al., 2007), prostaglandins (Almirza et al., 2012; Rodríguez-Lagunas et al., 2010), rotavirus NSP4 protein (Hagbom et al., 2012; Hyser et al., 2010) and bacterial toxins (Poppoff and Poulain, 2010; Timar Peregrin et al., 1999) also possess the potential to mobilize Ca2+ which involve extracellular Ca2+ influx and/or Ca2+ release from intracellular pools.

Fig. 1. Overview of evidence for Ca2+ signaling inhibition involved in anti-emetic actions of agents.

Please cite this article as: Zhong, W., et al., Ca2+ signaling and emesis: Recent progress and new perspectives, Auton. Neurosci. (2016), http:// dx.doi.org/10.1016/j.autneu.2016.07.006

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Much of the discussed evidence has been acquired from isolated cells. The least shrew (Cryptotis parva) is an emesis-competent mammal whose reactions to common emetogens are well-defined and correlate closely with human responses (Darmani and Ray, 2009). In our studies, incubation of isolated least shrew brainstem slices containing the DVC emetic loci with a specific emetogen, the selective 5-HT3R agonist 2Me-5-HT, results in a rapid increase in intracellular Ca2+ concentration as reflected by an increase in fluo-4AM fluorescence intensity in a palonosetron/nifedipine-sensitive manner (Hutchinson et al., 2015; Zhong et al., 2014b). 2.2. Emetic potential of Ca2+ channel activators A variety of Ca2+-permeable ion-channels mediating extracellular Ca2 + influx are present in the plasma membrane. Among them are voltage-gated L-type Ca2 + channels (LTCCs), which can be activated by membrane depolarization, and serve as the principal route of Ca2+ entry in electrically excitable cells such as neurons and muscle (Suzuki et al., 2009; Yoshimaru et al., 2009). Recently we have acquired direct evidence for the proposal that Ca2+ mobilization is an important facet in the mediation of emesis. In fact we have identified the novel emetogen FPL64176, a selective agonist of LTCCs, which causes vomiting in the least shrew in a dose-dependent manner (Darmani et al., 2014; Zhong et al., 2014a). All tested shrews vomited at the 10 mg/kg dose of FPL64176 administered intraperitoneally (i.p.). LTCCs have been shown to be present in enterochromaffin cells of guinea pig and human small intestinal crypts (Lomax et al., 1999). Furthermore, in these cells FPL64176 not only can enhance cytosolic Ca2 + concentration, but also it increases 5-HT release from them (Lomax et al., 1999). The latter findings may have underpinnings for the mechanisms underlying FPL64176-evoked vomiting observed in least shrew model of emesis. Our most recent work has focused on the Ca2 +-mobilizing agent thapsigargin (Fig. 2), a specific and potent inhibitor of the sarcoplasmic/endoplasmic reticulum Ca2+-ATPase (SERCA) pump which transports the free cytosolic Ca2+ into the lumen of SER to counter-balance the cytosolic intracellular Ca2+ release from the SER into the cytoplasm via the inositol trisphosphate receptors (IP3Rs) and ryanodine receptors (RyRs) (Garaschuk et al., 1997; Gómez-Viquez et al., 2003 and GómezViquez et al., 2010). Thapsigargin also causes intracellular release of stored Ca2+ from the SER into the cytosol which subsequently evokes extracellular Ca2+ influx predominantly through store-operated Ca2+ entry (SOCE) in non-excitable cells (Cheng et al., 2013; Feske, 2007; Parekh and Putney, 2005). In total, these events lead to a significant rise in the free concentration of cytosolic Ca2+ (Beltran-Parrazal et al., 2012; Michelangeli and East, 2011; Solovyova and Verkhratsky, 2003). In addition, a partial involvement of LTCCs in thapsigargin-evoked

Fig. 2. A schematic representation of extracellular Ca2+ influx and intracellular Ca2+ release contributing to thapsigargin-elicited Ca2+ mobilization. Intracellular Ca2+ release from the sarco/endoplasmic reticulum (SER) Ca2+ stores through the inositol triphosphate receptors (IP3Rs) and ryanodine receptors (RyRs) is counter-balanced by continuous Ca2+ uptake from the cytoplasm into SER stores by the SER Ca2+-ATPase pump (SERCA). Thapsigargin is a specific inhibitor of SERCA and thus enhances cytosolic levels of Ca2+, a process involving SER Ca2+ release via IP3Rs and RyRs as well as extracellular Ca2+ entry through Ca2+ channels located in the plasma membrane including store-operated Ca2+ channels (SOCE) and L-type Ca2+ channels (LTCCs).

3

contraction has also been demonstrated in rat stomach smooth muscle cells (Smaili et al., 1998), rat gastric smooth muscle (Van Geldre and Lefebvre, 2004), and cat gastric smooth muscle (Petkov and Boev, 1996). On the other hand, the potential of thapsigarign as a Ca2 +modulating cancer chemotherapeutic agent has been evaluated in both cells and animal models (Denmeade et al., 2003). Thapsigarginevoked increases in cytosolic Ca2+ concentration can lead to cell apoptosis, which can result in eradication of cancer cells of the breast (Jackisch et al., 2000), prostate (Dubois et al., 2013), colon (Yamaguchi et al., 2003) and kidneys (Lee et al., 2008). Clinically, a prodrug form of thapsigargin, mipsagargin, is currently under clinical trial as a targeted cancer chemotherapeutic agent with selective toxicity against cancer cells in tumor sites with minimal side-effects to the host (Denmeade et al., 2012; Denmeade and Isaacs, 2005; Denmeade and Isaacs, 2012; Doan et al., 2015). In our studies, intraperitoneal administration of thapsigargin (0.1–10 mg/kg) caused vomiting in least shrews in a dose-dependent, but bell-shaped manner, with maximal efficacy at 0.5 mg/kg. An important consideration for the emetic potential of thapsigargin is that it augments the cytosolic levels of free Ca2 + in emetic loci as a result of SERCA inhibition as indicated in our latest discussed finding (Zhong et al., 2016), which is the first study to reflect emesis as a major side-effect of thapsigargin when delivered systemically. 3. Ca2 + intervention: mechanisms and potential therapeutic approaches 3.1. Receptor antagonist antiemetic regimens such as NEPA The ultimate aim of prophylactic management of CINV is to abolish both the acute- and delayed phases of vomiting which will help improve the well-being and quality of life of cancer patients receiving chemotherapy. Cisplatin-like chemotherapeutics cause release of multiple emetogenic neurotransmitters in both the CNS and the GIT, and currently no available single antiemetic administered alone can provide complete efficacy. Significant initial work had suggested that while activation of 5-HT3Rs by serotonin in the GIT is involved in the mediation of acute phase of CINV, the delayed phase was due to stimulation of NK1Rs subsequent to release of SP in the brainstem (Andrews and Rudd, 2004; Hesketh et al., 2003a). However, more recent evidence suggest that 5-HT and SP are concomitantly involved in both emetic phases in the GIT as well as in the CNS (Darmani et al., 2009; Darmani and Ray, 2009). While netupitant is a highly selective and longer-acting second generation NK1R antagonist, palonosetron is considered as a second generation 5-HT3R antagonist with a unique antiemetic profile in both humans (Hesketh et al., 2014; Gralla et al., 2014) and the least shrew model of emesis (Darmani et al., 2015). A successful regimen of an oral fixed combined dose of netupitant/palonosetron (NEPA) has been formulated with over 85% clinical efficacy, good tolerability, and high CNS penetrance for the prophylactic treatment of acute and delayed CINV in cancer patients receiving chemotherapy (Hesketh et al., 2015; Keating, 2015; Rojas and Slusher, 2015). Recent evidence accumulated from HEK293 cells stably transfected with 5-HT3Rs suggest that suppression of Ca2+ signaling is involved in antiemetic efficacy of both palonosetron and netupitant. Indeed, Rojas et al. (2008, 2010a) have shown that palonosetron causes a persistent inhibition of 5-HT3R function as reflected by a near complete suppression of 5-HT-evoked extracellular Ca2+ influx. They have further demonstrated that palonosetron can prevent enhancement of SP-induced intracellular Ca2+ release in response to serotonin in NG108-15 cells expressing both 5-HT3Rs and NK1Rs (Rojas et al., 2010b). Our Ca2+ monitoring studies performed on acutely-prepared least shrew brainstem slices also demonstrate that palonosetron can abolish enhancement of intracellular Ca2+ levels in brainstem slices evoked by the selective 5HT3R agonist 2-Me-5-HT (Zhong et al., 2014b). The latter finding provides more relevant ex-vivo evidence for the Ca2 +-modulating

Please cite this article as: Zhong, W., et al., Ca2+ signaling and emesis: Recent progress and new perspectives, Auton. Neurosci. (2016), http:// dx.doi.org/10.1016/j.autneu.2016.07.006

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antiemetic effect of palonosetron in a vomit-competent species. The role of netupitant in suppression of SP-evoked enhancement of intracellular Ca2+ levels has also been demonstrated via Ca2+ mobilization assays in vitro in CHO cells expressing the human NK1Rs. Moreover, pronetupitant, an intravenous alternative to the oral netupitant, appears to be more potent than netupitant in both in vitro Ca2+ measurement studies and in vivo animal behavioral evaluations of SP in rats (Rizzi et al., 2012; Ruzza et al., 2015). Another approved NK1R antagonist antiemetic rolapitant, has also been shown to suppress the ability of the selective NK1R agonist GR73632 to evoke intracellular Ca2+ release (Chasen and Rapoport, 2016; Duffy et al., 2012; Rapoport et al., 2015; Rojas and Slusher, 2015). 3.2. Cannabinoid CB1 receptor agonists Before the introduction of first generation 5-HT3R antagonists, several phyto- and synthetic cannabinoids including dronabinol (delta-9tetrahydrocannabinol, Δ9-THC), levonantradol and nabilone, were evaluated in cancer patients for suppression of CINV that were not effectively controlled by other available antiemetics (Darmani and Ray, 2009; Todaro, 2012). Cannabinoids are increasingly being used as antiemetics against cisplatin-induced emesis in animal experiments using house musk shrews (Bolognini et al., 2013), ferrets (Van Sickle et al., 2001), or least shrews (Ray et al., 2009b; Wang et al., 2009), nausea-related behavior in rats (Bolognini et al., 2013), radiation-induced emesis in the least shrew (Darmani et al., 2007), as well as both phases of CINV in the clinic (Pertwee, 2012; Punyamurthula et al., 2015; Tafelski et al., 2016). Such cannabinoids exert their antiemetic efficacy via direct activation of CB1 receptors (CB1R) since their antiemetic effects were reversed by CB1R antagonists (Darmani et al., 2007; Parker et al., 2011; Van Sickle et al., 2001 and Van Sickle et al., 2003; Ware et al., 2008). Significant evidence for a role for CB2Rs in emesis is currently lacking (Sharkey et al., 2014). The presence of CB1Rs in the brainstem nuclei involved in emesis has been confirmed, with a high density of CB1R immunoreactivity in the DMNX and the medial subnucleus of the NTS, a moderate density in the commissural subnucleus of the NTS, and lower densities in the AP and dorsal subnucleus of the NTS (Ray et al., 2009b; Van Sickle et al., 2001). CB1R distribution has been also observed in the myenteric plexus of the stomach and duodenum (Van Sickle et al., 2001). Furthermore, CB1Rs have been localized in the myenteric plexi of the rat and guinea pig intestine in nearly all cholinergic neuron terminals (Darmani, 2006; Galligan, 2009). These as well as behavioral evidence (Darmani and Johnson, 2004) suggest that the anti-emetic action of cannabinoids involves both the central DVC and intestinal emetic loci. In addition, primary cultures of guinea-pig myenteric neurons express CB1Rs at their terminals and exogenously added cannabinoids suppress their neuronal activity, synaptic transmission and mitochondrial transport along axons (Boesmans et al., 2009). Moreover, the CB1/2R agonist WIN55212-2 can suppress intestinal activity since it can attenuate the electrically-evoked contractions of the myenteric plexus-longitudinal muscle preparation of the guinea-pig small intestine in a Ca2 +-dependent and CB1R-specific manner (Coutts and Pertwee, 1998). Thus, CB1R agonists in the in vivo setting can also suppress gastrointestinal tract motility (Boesmans et al., 2009). Using whole-cell patch-clamp recordings in brainstem slices, Derbenev et al. (2004, 2006) have shown that activation of presynaptic CB1Rs in the DVC inhibits synaptic transmission to DMNX neurons, which may explain suppression of visceral motor responses caused by cannabinoids. Furthermore, in the central nervous system CB1R stimulation can result in inhibition of Ca2+-dependent neurotransmitter release from presynaptic nerve terminals which consequently leads to an inhibition of neurotransmission (Szabo and Schlicker, 2005). In CINV, the CB1Rmediated antiemetic action of cannabinoids appears to be directly related to presynaptic inhibition of release of emetic neurotransmitters from nerve terminals. The following evidence may help explain the antiemetic action of cannabinoid CB1R agonists from the Ca2 + perspective

Fig. 3. A schematic explanation of the antiemetic action of cannabinoid CB1R agonists from the Ca2+ perspective. Activation of CB1R initiates a Gi/o mechanism leading to the downregulation of extracellular Ca2+ influx through voltage-gated Ca2+ channels (VGCCs) as well as endoplasmic reticulum (ER) Ca2+ release via ryanodine receptors (RyRs) which is potential to be activated by extracellular Ca2+ entry through VGCCs. The reduction in cytosolic Ca2+ attenuates Ca2+-dependent emetic neurotransmitter release, further results in a reduction in postsynaptic neuronal activation, and ultimately suppressed the vomiting behavior.

(Fig. 3). The adenylyl cyclase/cyclic AMP (cAMP)/protein kinase A (PKA) signal transduction system is a well-established emetic signaling pathway (Alkam et al., 2014). PKA activation is known to phosphorylate both Ca2+ ion channels on plasma membrane and intracellular endoplasmic IP3Rs, which respectively increase extracellular Ca2 + influx and internal Ca2+ release from the SER stores (Yao et al., 2008). CB1Rs are known to be Gi/o-protein coupled receptors which mediates inhibition of adenylate cyclase. This inhibition has been proposed to be the fundamental reason for CB1R agonists attenuating Ca2 +-dependent emetic neurotransmitter release which would ultimately reduce postsynaptic neuronal activation in both DVC and GIT (Galligan, 2009; Wang et al., 2009). Dose-dependent inhibitory action of cannabinoid CB1R agonists such as WIN55212-2 on extracellular Ca2+ influx via a number of voltage-gated Ca2+ channels residing in the cell membrane including N-type, P/Q type and L-type have been shown in multiple experimental systems (Lalonde et al., 2006; Lozovaya et al., 2009; Straiker et al., 1999; Straiker and Sullivan, 2003; Yang et al., 2016). Moreover, cannabinoid CB1R agonists also block 5-HT3Rs in a non-competitive manner and thus prevent extracellular Ca2 + influx (Shi et al., 2012; Yang et al., 2016). Moreover, CB1R agonists appear to inhibit the internal Ca2+ release channels located on the SER membrane, RyRs. Ca2+-induced Ca2+ release (CICR) is a well-established feature of Ca2+ signal amplification. During neuronal activation, CICR Ca2+ signaling involves increased concentration of cytoplasmic Ca2 + via extracellular Ca2+ influx through voltage-gated Ca2 + channels (e.g., LTCCs) present on the cell membrane, which then causes release of stored intracellular Ca2+ from the SER into the cytosol through RyRs (Galeotti et al., 2008). In addition, RyRs have a wide distribution in the central nervous system including the brainstem (Ledbetter et al., 1994). RyRs not only can regulate Ca2+ homeostasis, but also other critical brain functions including neurotransmitter release (Galeotti et al., 2008). An increased serum level of the proinflammatory cytokine, tumor necrosis factor alpha (TNF-α), is associated with chemotherapy-evoked vomiting (Martin et al., 2014). TNF-α can excite vagal afferent terminals by augmenting Ca2+ release from SER stores via sensitization of RyRs which subsequently amplifies neurotransmission in the brainstem (Rogers and Hermann, 2012). Cannabinoid CB1R agonists prevent the TNF-α-evoked sensitization of RyRs

Please cite this article as: Zhong, W., et al., Ca2+ signaling and emesis: Recent progress and new perspectives, Auton. Neurosci. (2016), http:// dx.doi.org/10.1016/j.autneu.2016.07.006

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and therefore attenuate intracellular Ca2+ release from the SER stores (Rogers and Hermann, 2012). Peripheral RyRs also play a critical role in agonist-evoked Ca2+ oscillations in gut epithelial cells (Verma et al., 1996). Therefore, the ability of CB1R agonists in preventing both extracellular Ca2+ influx as well as intracellular Ca2+ release from SER stores may be the fundamental mechanisms underlying the broad-spectrum antiemetic efficacy of such agents. Despite the approved use of CB1R agonists for medical purposes, their use still remains legally and therapeutically controversial. With safer and more effective antiemetic NEPA available, currently CB1R agonists are not recommended as first- or second-line treatment for nausea and vomiting (Tafelski et al., 2016). 4. Perspective in developing new antiemetic candidates 4.1. Antiemetic efficacy of LTCC blockers in the least shrew model of emesis Our previous studies have demonstrated that the least shrew is an appropriate animal model for studying the emetic activity of diverse agents (Darmani and Ray, 2009). 2-Me-5HT is a well-known selective emetic agonist targeting the emesis-prone 5-HT3Rs (Ray et al., 2009a). The least shrew species exhibits dose-dependent full emetic responses to the intraperitoneal administration of the peripherally-acting 5-HT, as well as to its CNS-penetrating analog, 2-Me-5-HT (Darmani, 1998; Darmani and Johnson, 2004; Ray et al., 2009a). The DVC and the GIT are important central and peripheral sites for the emetic action of 2Me-5-HT as indicated by increased c-fos-like immunoreactivity observed in the AP, NTS, DMNX, and dorsal raphe nucleus (DRN), as well as the enteric nervous system (ENS), respectively (Ray et al., 2009a). We have recently found that blockade of voltage-gated LTCCs by its antagonist nifedipine, can fully suppress the 2-Me-5-HT-evoked enhancement in intracellular Ca2+ levels monitored in least shrew brainstem slices (Hutchinson et al., 2015; Zhong et al., 2014b). As described above (see Section 2.2), the LTCC activator FPL64176 is a fully efficacious emetogen in the least shrew at 10 mg/kg intraperitoneal dose. Human duodenal enterochromaffin (EC) cell exposure to FPL64176 not only increases intracellular Ca2+ concentration, but can also release 5-HT from these cells (Lomax et al., 1999), which is a Ca2 +-dependent process (Racke et al., 1996). Furthermore, 5-HT release from EC cells can be suppressed by antagonists of both 5-HT3Rs and LTCCs (Minami et al., 2003a and Minami et al., 2003b). Nifedipine along with amlodipine, are among the most studied of Ca2+ channels blockers, and both belong to the dihydropyridine subgroup of LTCC antagonists. Due to its unique structural features including the replacement of the nitro substituent in nifedipine with a chlorine and a side chain with a basic substituent, amlodipine molecules exist primarily in the ionized form at physiologic PH (Abernethy, 1991). Therefore, relative to nifedipine, a short-acting LTCC antagonist with a plasma half-life of 1.2 h (Burges and Moisey, 1994); amlodipine is longer acting, more extensively bound to plasma protein, with a larger volume of distribution, more gradual elimination, with a half-life of over 30 h (Abernethy, 1991; Burges, 1991; Burges and Moisey, 1994; Reid et al., 1988; Toal et al., 2012). Amlodipine also slowly associates with and dissociates from L-type calcium channel in a manner 2–3 orders of magnitude slower than other dihydropyridines (Burges et al., 1989; Burges and Moisey, 1994). Furthermore, amlodipine displays a gradual potency increase from 1 (Ki 3.1 nM) to 3 h (Ki 1.3 nM) (Burges et al., 1989; Burges and Moisey, 1994). Moreover, 3.5 h after incubation, amlodipine appears to be twice potent as nifedipine (IC50: 1.9 nM for amlodipine; 4.1 nM for nifedipine), while nifedipine reached to its maximal effect within 30 min (Burges et al., 1989; Burges and Moisey, 1994). In addition, peak plasma levels occurs 6–12 h after oral dosing of amlodipine (Reid et al., 1988). We have evaluated the antiemetic efficacy of nifedipine and amlodipine by assessing mean emesis frequency and the percentage of shrews vomiting, and demonstrated that both LTCC blockers (Darmani et al., 2014; Zhong et al., 2014a) behave as

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broad-spectrum antiemetics when delivered systemically against diverse specific emetogens, including FPL 64176 (10 mg/kg, i.p.), the peripherally-acting and non-selective 5-HT3R agonist 5-HT (5 mg/kg, i.p.), the peripherally/centrally-acting and more selective 5-HT3R agonist 2-Me-5-HT (5 mg/kg, i.p.), the dopamine D2R-preferring agonist quinpirole (2 mg/kg, i.p.), the non-selective dopamine D2R agonist apomorphine (2 mg/kg, i.p.), the nonselective cholinergic agonist pilocarpine (2 mg/kg, i.p.), the M1-preferring cholinergic agonist McN-A343 (2 mg/kg, i.p.), and the selective tachykinin NK1R agonist GR73632 (5 mg/kg, i.p.). In our latest investigation, the LTCC antagonist nifedipine, also protected 50% of shrews from thapsigargin-evoked vomiting and reduced the mean vomit frequency by 85% at 2.5 mg/kg, whereas its 5 mg/kg dose nearly completely suppressed the vomit frequency and protected over 90% of tested shrews (Zhong et al., 2016). As seen from ID50s shown in Table 1, both dihydropyridine analogs were equipotent against emesis caused by apomorphine, and only amlodipine was able to significantly suppress vomiting caused by pilocarpine. Nifedipine appears to be 2–24 times more potent than amlodipine against vomiting caused by FPL64176, 5-HT, 2-Me-5-HT, GR73632, quinpirole and McN-A343. These potency disparities could be explained in terms of their pharmacokinetic and pharmacodynamic differences. As discussed earlier, nifedipine has a rapid onset of action and reaches peak plasma concentration within 30 min of administration with a short duration of action (Croom and Wellington, 2006; Meredith and Reid, 1993). On the other hand, amlodipine has a long duration of action and reaches peak plasma concentration between 6 and 8 h with a slow onset of action (Burges and Dodd, 1990; Nayler and Gu, 1991). Since both antiemetics were administered 30 min prior to the administration of the discussed emetogens, it is likely that amlodipine may not have had sufficient time to reach its sites of action, thus having lower potency. Nevertheless, the equipotent antiemetic efficacy of amlodipine and nifedipine against apomorphine was surprising since amlodipine is less potent than nifedipine against vomiting caused by the dopamine D2R preferring agonist, quinpirole. A further enigma is the inability of nifedipine at relatively large doses to suppress vomiting caused by the nonselective cholinergic agonist pilocarpine, whereas amlodipine was fully effective in suppressing the frequency and percentage of shrews vomiting in response to pilocarpine, versus the greater relative potency of nifedipine against vomiting caused by the more selective cholinergic M1 agonist, McN-A343. These paradoxes cannot be easily explained in terms of pharmacokinetic/pharmacodynamic differences. However, the efficacy of amlodipine and lack of antiemetic action of nifedipine against cisplatin (10 mg/kg., i.p.)-induced vomiting can be explained in terms of amlodipine's pharmacokinetic and pharmacodynamic profiles. Unlike the above tested emetogens which can evoke vomiting within minutes of administration, cisplatin (10 mg, i.p.) requires more exposure time (30–45 min) to begin to induce emesis since only its metabolites are emetogenic (Mutoh et al., 1992). The relative efficacy of amlodipine (5 mg/kg., i.p.) in reducing the frequency of cisplatin-evoked vomiting by 80% compared with the observed lack of antiemetic action of nifedipine up to 20 mg/kg (Darmani et al., 2014; Zhong et al., 2014a), could be explained in terms of positively charged amlodipine associating more slowly with LTCCs, requiring more exposure time not only to reach its sites of action, but also to compensate for its slower receptor binding kinetics, which can lead to a more gradual onset of antagonism (Qu et al., 1996). Another potential contributing factor for the efficacy of amlodipine against cisplatin-induced vomiting is its ability to bind an additional Ca2+ site (Burges and Moisey, 1994). In addition, intracerebroventricular microinjection of another LTCC antagonist, nitrendipine, has been shown to attenuate nicotine-induced vomiting in the cat (Samardzic et al., 1999); which further supports the discussed broad-spectrum antiemetic efficacy of nifedipine and amlodipine as observed in the least shrew model. One shortcoming in the discussed cisplatin studies is that the antiemetic effect of amlodipine was observed for 4 h following cisplatin administration. Cisplatin-based

Please cite this article as: Zhong, W., et al., Ca2+ signaling and emesis: Recent progress and new perspectives, Auton. Neurosci. (2016), http:// dx.doi.org/10.1016/j.autneu.2016.07.006

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Table 1 Respective antiemetic ID50 values for amlodipinea and nifedipineb against vomiting caused by diverse emetogens. Emetogens

FPL 64176 5-HT 2-Me-5-HT Apomorphine Quinpirole Pilocarpine McN-A-343 GR73632

Amlodipine ID50 (mg/kg)

Nifedipine ID50 (mg/kg)

Frequency

Percent inhibition

Frequency

Percent inhibition

1.10 (0.43–2.80) 2.00 (0.80–5.20) 0.65 (0.30–1.40) 0.90 (0.30–2.60) 2.00 (0.78–5.30) 2.10 (0.69–6.20) 2.30 (0.61–8.50) 1.37 (0.62–3.00)

2.70 (1.40–5.30) 3.20 (1.60–6.50) 3.10 (1.40–6.60) 2 0.00 (0.94–4.30) 4.40 (1.90–10.0) 4.60 (2.20–9.40) 3.20 (1.50–7.10) 7.10 (3.40–14.6)

0.31 (0.15–0.62) 0.22 (0.03–1.50) 0.053 (0.02–0.17) 0.91 (0.32–2.60) 0.10 (0.03–0.36) nd 0.38 (0.06–2.30) 0.19 (0.08–0.43)

0.42 (0.19–0.90) 0.91 (0.42–1.90) 1.34 (0.64–2.80) 2.02 (0.90–4.40) 0.18 (0.09–0.38) nd 0.95 (0.43–2.10) 0.60 (0.28–1.30)

ID50 values were calculated using non-linear regression analysis (Graph Pad PRISM version 6). nd = not determined. a Obtained from Zhong et al., 2014a. b From Darmani et al., 2014.

chemotherapeutics induce both immediate and delayed vomiting in humans and in vomit-competent animals (Darmani et al., 2009; Hesketh et al., 2003b; Rudd and Andrews, 2005). In the least shrew, cisplatin (10 mg/kg, i.p.) causes emesis over 40 h with respective peak early- and delayed-phases occurring at 1–2 and 32–34 h postinjection (Darmani et al., 2015). Amlodipine, due to its unique pharmacokinetics, may offer practical advantages over other calcium antagonists in the cisplatin-caused delayed emesis. One of our ongoing projects is focusing on the anti-emetic efficacy of amlodipine as well as combination of palonosetron/netupitant with amlodipine at noneffective doses against cisplatin-induced vomiting over the 40-hour period post cisplatin treatment on least shrews. One question that requires consideration is that how connected/disconnected are the activation of calcium signaling and subsequent emetic response with the anticancer properties for the potential cancer chemotherapeutics? Cisplatin, one of the most potent and clinically important chemotherapy agents, is a platinum chemotherapeutic used in a variety of malignancies in human and veterinary medicine. Cisplatin is generally considered to kill cancer cells by damaging DNA and inhibiting DNA synthesis, which induces mitochondria-mediated apoptosis and consequently, cell death (Barabas et al., 2008; Shen et al., 2016). More recent findings reveal that cisplatin triggers apoptotic events via endoplasmic reticulum (ER) stress (Shen et al., 2016). As discussed earlier the sarcoplasmic/endoplasmic reticulum (SER) [SER = ER] is one major intracellular organelle that stores Ca2 + and controls free cytosolic calcium levels. Thus, both induction of emesis as well as apoptosis involve changes in extracellular Ca2 + influx as well as intracellular Ca2+ release (Al-Taweel et al., 2014; Shen et al., 2016). However, the extent of involvement of cisplatin-evoked shared signals between the emetic and apoptotic processes downstream of Ca2+ signaling remains to be elucidated. Likewise, as discussed in the present manuscript thapsigargin-evoked emetic and apoptotic effects also involve intracellular calcium release, however the extent of shared signals between these processes downstream of Ca2+ signaling requires further research. 4.2. Potentiation of anti-emetic efficacy of 5-HT3R antagonists when combined with LTCC blockers Since extracellular Ca2+ influx appears to be a prerequisite component of vomiting and serotonin 5-HT3Rs and LTCCs allow such Ca2+ influx, we envisaged concomitant blockade of these Ca2+-permeable ion channels by corresponding antagonists should provide additive antiemetic protection. As a matter of fact when non-effective antiemetic doses of nifedipine and palonosetron were combined (Darmani et al., 2014), the combination significantly and in synergistic manner attenuated both the frequency and the percentage of shrews vomiting in response to FPL 64176 or 2-Me-5-HT. Furthermore, nifedipine at its 0.5 mg/kg dosage significantly potentiated the antiemetic efficacy of a

non-effective (0.025 mg/kg) as well as a semi-effective (0.5 mg/kg) dose of palonosetron against cisplatin-induced acute vomiting. In another study a combination of non-effective doses of amlodipine (0.5 mg/kg or 1 mg/kg) with a non- or semi-effective dose of the 5HT3R antagonist palonosetron (0.05 or 0.5 mg/kg) produced a similar additive efficacy against vomiting evoked by either FPL 64176 or cisplatin (Zhong et al., 2014a). The observed additive antiemetic efficacy of a combination of 5-HT3- (and/or possibly NK1-) with L-type Ca2+ channel antagonists in the least shrew suggests that such a combination should provide greater emesis protection in cancer patients receiving chemotherapy in a manner similar to that reported when 5-HT3- and NK1receptor antagonists are combined both in the laboratory (Darmani et al., 2011; Darmani et al., 2015) and in the clinic (Warr, 2012). Thus, the broad-spectrum antiemetic potential of both nifedipine and amlodipine against the diverse selective and nonselective emetogens in the least shrew further supports our proposed Ca2+ hypothesis and provides evidence for initiation of clinical trials to determine of clinically-useful LTCC antagonist antiemetics. 4.3. Clinical use of L-type Ca2+ channel blockers as anti-nausea/anti-emetic medication There are several published clinical case reports that demonstrate that Ca2 + channel blockers may provide protection against several causes of nausea and vomiting. The LTCC antagonist flunarizine was shown to reduce cyclic vomiting on acute basis in one patient (van Driessche et al., 2012) and prophylactically in 8 other patients (Kothare, 2005). Gabapentin is a gamma-aminobutyric acid (GABA) analog and is predominantly used in the clinic for the management of pain (Guttuso, 2014). Though originally designed as analogs of GABA, gabapentin has any significant agonist-like effect on GABAA or GABAB receptors, and no obvious effects on the levels of GABA. Gabapentin binds to the alpha-2/delta auxiliary subunits of voltage gated calcium channels (VGCCs), and exerts inhibitory actions on trafficking and activation kinetics VGCCs (Patel and Dickenson, 2016). Several reports indicate that gabapentin can also be used as a well-tolerated, less-expensive and promising anti-nausea and anti-emetic agent in diverse conditions including: postoperative nausea and vomiting (Achuthan et al., 2015; Memari et al., 2015), moderately or highly emetogenic CINV, particularly effective against delayed CINV (Cruz et al., 2012) and both acute and delayed nausea induced by chemotherapy (Guttuso et al., 2003), and hyperemesis gravidarum (Guttuso et al., 2010). When combined with dexamethasone, gabapentin can also significantly reduce the 24-hour incidence of postoperative nausea and vomiting (Misra et al., 2013). Alpha-2/delta subunits of VGCCs control transmitter release and further facilitate excitatory transmission (Patel and Dickenson, 2016). Gabapentin's interaction with neuronal alpha-2/delta subunits of VGCCs and subsequent downregulation of neuronal Ca2+ signaling in emesis relevant sites, such as the DVC, is postulated to play a critical

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role in its anti-nausea and anti-vomiting effects (Guttuso, 2014). The Ntype voltage-sensitive Ca2 + channel predominantly controls neurotransmitter release from presynaptic nerve terminals and is involved in nociception (Zamponi et al., 2015). A blocker of N-type Ca2+ channels, ziconotide, has been shown to suppress chronic pain in clinical trials (Williams et al., 2008) and such blockers may have the potential to be antiemetic. However, zoconitide administration can evoke significant nausea and vomiting in chronic pain patients. To date the emetic/ antiemetic potential of other N-type calcium blockers has not been investigated in either patients or in animal models of emesis. It warrants mention other potential and/or established clinical uses for Ca2+ antagonists besides their anti-nausea/anti-emetic potential. LTCC inhibitors appear to attenuate blood pressure to normal basal levels in hypertensive animals and patients, but do not affect the blood pressure of normotensive animals and patients (Malhotra et al., 2001; Mehsen et al., 2011; Nayler, 1988). More importantly, upregulation of functional activation and/or expression of plasma-membrane Ca2 + channels, consequently elevate Ca2 + entry which can affect Ca2+-dependent signaling processes (Cheng et al., 2013; Feske, 2007; Parekh and Putney, 2005). In fact, it has been proposed that increased Ca2+ signaling may be responsible for tumorigenesis and cancer multiplication, migration and invasion (Déliot and Constantin, 2015; Xie et al., 2016). Indeed, carboxyamidotriazole, an inhibitor of nonvoltage-dependent Ca2+ channels, which subsequently suppresses the intracellular Ca2 + release and Ca2 +-dependent signal transduction pathways (Lodola et al., 2012), has been shown to possess growth inhibitory effects on a broad array of human tumor cell lines and is clinically effective in inhibiting angiogenesis, tumor growth, invasion, and metastasis of various cancers (Perabo et al., 2004; Kohn et al., 1996). It has also clinical potential as a maintenance therapeutic agent in the stabilization of relapsed ovarian cancer (Hussain et al., 2003). Thus, it is important to understand Ca2 + mechanisms beyond chemotherapyinduced nausea and vomiting, and develop intervening regimens which can improve not only the efficacy of the next generation of antiemetics but antitumor therapy outcomes as well. One stumbling block in developing LTCC blockers such as amlodipine for new indications for the clinic (such as vomiting) is that these agents are out of patent and pharmaceutical companies are not interested in further research investment. To bypass this hurdle, one could design new agents to “selectively” target Ca2 + channels both in the plasma membrane (e.g. LTCCs and 5-HT3Rs) and the ER membrane (such as RyR and IP3Rs). 4.4. Internal Ca2+ release channels: Possible targets in preventing emesis A functional and physical linkage between LTCCs and RyRs appears to exist which plays an important role in intracellular Ca2+ release following voltage-dependent Ca2+ entry through LTCCs during neuronal depolarization to generate a transient increase in cytosolic Ca2 + (Berrout and Isokawa, 2009; Katoh et al., 2000; Resende et al., 2010). Physical attachment of IP3Rs to plasma membrane Ca2+ influx channels through conformational coupling has also been proposed as one of the mechanisms connecting depletion of internal Ca2+ stores with stimulation of extracellular Ca2+ influx (Li et al., 2003). For example, Ca2+ release from IP3Rs was shown to couple with extracellular Ca2 + influx through LTCCs in non-excitable cells such as Jurkat human T lymphocytes (Wang and Wu, 2011) and drosophila S2 cells (Wang et al., 2015), as well as in excitable cells such as submucosal neurons in the rat distal colon (Rehn et al., 2013). We have found that 5-HT3Rmediated vomiting triggered by 5 mg/kg 2-Me-5HT is insensitive to the intracellular Ca2+ release channel IP3R antagonist 2-APB, but in contrast, was dose-dependently suppressed by the RyR antagonist, dantrolene. Furthermore, a combination of the semi-effective doses of amlodipine and dantrolene was more potent than each antagonist being tested alone (Zhong et al., 2014b). These behavioral findings suggest that 5-HT3R stimulation drives extracellular Ca2+ through both L-

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type Ca2+ channels and 5-HT3Rs, which leads to Ca2+-induced Ca2+release (CICR) from intracellular SER stores via RyRs, and subsequently greatly amplifies free Ca2+ levels in the cytoplasm. These in vivo findings are in line with previous in vitro cellular evidence that 5-HT3R activation evokes extracellular Ca2+ entry which then triggers such Ca2+ release from intracellular stores in a RyR-sensitive manner (Ronde and Nichols, 1997). Significant reductions (70–85%) in the frequency of Ca2+ mobilizer thapsigargin-evoked vomiting (see Section 2.2) were observed when shrews were pretreated with antagonists of either IP3Rs (2-APB at 1 and 2.5 mg/kg, i.p.)- or RyRs (dantrolene at 2.5 and 5 mg/kg, i.p.)-ER luminal Ca2 + release channels. Moreover, while a mixture of 2-APB (1 mg/kg) and dantroline (2.5 mk/kg) did not offer additional protection than what was afforded when each drug administered alone, a combination of the latter doses of 2-APB plus dantrolene with a 2.5 mg/kg dose of nifedipine, led to a complete elimination of thapsigargin-evoked vomiting. Thus, our study provides in vivo evidence that the SERCA inhibiting agent thapsigargin causes vomiting in a process dependent upon Ca2+ signaling which includes Ca2+ store release through IP3Rs and RyRs, as well as LTCC-facilitated extracellular Ca2 + entry. The discussed findings suggest that suppression of SER store Ca2+ release through IP3Rs and RyRs may be additional targets for the treatment of nausea and vomiting.

5. Conclusion Chemotherapy-induced nausea and vomiting is a particularly distressing event for oncology patients both physically and psychologically. The use of 5-HT3R antagonists combined with NK1R antagonists, has enhanced physician's ability to further suppress nausea, the rates of acute and delayed vomiting in cancer patients receiving chemotherapy. In addition to the commonly reported adverse effects of these agents (including headache, diarrhea, constipation, hiccups, and fatigue), many patients' still experience nausea and delayed vomiting (Navari, 2016; Slatkin, 2007; Sommariva et al., 2016). Furthermore, the use of second generation 5-HT3R and NK1R antagonists for the prevention of CINV is currently cost-prohibitive for most patients in the world. Mechanisms that cause nausea are only partially understood and probably in part overlap with those of vomiting. There are still unmet needs for newer and less expensive therapeutic options to improve the treatment across the entire spectrum of CINV. Additional studies should involve combinations of agents that inhibit other neurotransmitter systems involved in nausea and vomiting. As concluded in Fig. 1, this systematic review shows clear evidence that Ca2 + modulation is an important contributor to antiemetic and probably anti-nausea signaling pathways and LTCC blockers as well as antagonists of intracellular IP3Rs and RyRs Ca2+ release channels have the potential to provide less expensive (e.g. nifedipine, amlodipine and dantrolene) broad-spectrum antiemetic agents for the clinic against diverse causes of nausea and vomiting. The discussed findings from the least shrew should help open new avenues of research in other established animal models of emesis as well as in patients, targeting not only the already discussed Ca2+ channels, but also other Ca2+ channels that exist on both the plasma membrane and the membranes of intracellular organs such as the SER and mitochondria.

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Please cite this article as: Zhong, W., et al., Ca2+ signaling and emesis: Recent progress and new perspectives, Auton. Neurosci. (2016), http:// dx.doi.org/10.1016/j.autneu.2016.07.006