Regulation of KATP channel by 17β-estradiol in pancreatic β-cells

Steroids 76 (2011) 856–860

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Review

Regulation of KATP channel by 17␤-estradiol in pancreatic ␤-cells Sergi Soriano ∗ , Cristina Ripoll, Esther Fuentes, Alejandro Gonzalez, Paloma Alonso-Magdalena, Ana B. Ropero, Ivan Quesada, Angel Nadal ∗∗ Instituto de Bioingeniería and CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Universidad Miguel Hernández de Elche, 03202 Elche, Alicante, Spain

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Article history: Available online 4 April 2011 Keywords: Islet of Langerhans Insulin Estrogen Ion channels

a b s t r a c t ATP-sensitive potassium channels (KATP ) regulate electrical activity and insulin secretion in pancreatic ␤-cells. When glucose concentration increases, the [ATP]/[ADP] ratio rises closing KATP channels, and the membrane potential depolarizes, triggering insulin secretion. This pivotal role of KATP channels is used not only by glucose but also by neurotransmitters, hormones and other physiological agents to modulate electrical and secretory ␤-cell response. In recent years, it has been demonstrated that estrogens and estrogen receptors are involved in glucose homeostasis, and that they can modulate the electrical activity and insulin secretion of pancreatic ␤cells. The hormone 17␤-estradiol (E2), at physiological levels, is implicated in maintaining normal insulin sensitivity for ␤-cell function. Long term exposure to E2 increases insulin content, insulin gene expression and insulin release via the estrogen receptor ␣ (ER␣), while rapid responses to E2 can regulate KATP channels increasing cGMP levels through the estrogen receptor ␤ (ER␤) and type A guanylate cyclase receptor (GC-A). This review summarizes the main actions of 17␤-estradiol on KATP channels and the subsequent insulin release in pancreatic ␤-cells. © 2011 Elsevier Inc. All rights reserved.

Contents 1. 2. 3. 4. 5. 6.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The KATP channels comprise two subunits . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The location of KATP channel in the ␤-cell . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . KATP channel regulation by physiological agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . How does estradiol modulate KATP channel in pancreatic ␤-cells? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Concluding remark . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction ATP-sensitive potassium channels (KATP ) were first described in cardiac muscle by Noma in 1983 [1]. They perform a variety of functions, depending on the tissue where they are expressed, namely: the regulation of neuronal excitability [2], modulating vascular smooth muscle tone [3], promoting neuronal degeneration [4], regulating element to cardiac ischemia and stress adaptation [5] as well as an important role in appetite control [6,7].

∗ Corresponding author. Tel.: +34 965222164; fax: +34 965222033. ∗∗ Corresponding author. Tel.: +34 965222002; fax: +34 965222033. E-mail addresses: [email protected] (S. Soriano), [email protected] (A. Nadal). 0039-128X/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.steroids.2011.03.017

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In pancreatic ␤-cells, KATP channels play a crucial role in glucose stimulated insulin secretion (GSIS) [8]. At low glucose concentrations, KATP channels are open and the resting potential of pancreatic ␤-cells remains close to −70 mV. When blood glucose levels increase, the [ATP]/[ADP] ratio rises, as well as cGMP and other important regulators of stimulus–secretion coupling [9,10], closing the KATP channels. As a consequence, the membrane potential depolarizes up to about −40 mV, opening voltage dependent calcium channels (VDCC) and inducing Ca2+ influx, which, in turn, activates insulin secretion. 2. The KATP channels comprise two subunits Cloning KATP channels has permitted a better understanding of the molecular identity, structure and topology of this channel

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[11,12]. KATP channels are composed of four Kir6.x type subunits and four sulfonylurea (SUR) receptor subunits. There are two Kir6.x isoforms, kir 6.1 and kir 6.2 as well as two SUR isoforms, SUR1 and SUR2, the latter of which has two splice variants, SUR2A and SUR2B [13–15]. Kir6.2 and SUR2A are expressed in cardiac myocytes, whereas Kir6.2/kir6.1 and SUR2B are present in vascular smooth muscles and kir6.2 and SUR1/2B in central neurons [16]. The KATP channel is an octameric complex containing four molecules each of Kir6.2 and SUR1 in pancreatic ␤-cells and neuronal cells [15]. The sulfonylurea receptor SUR1 is a member of the ATP binding cassette (ABC) protein family [11] and it comprises the regulatory subunit. SUR1 contains 17 putative transmembrane domains and two potential nucleotide-binding domains (NBD1 and NBD2) whereas Kir6.2 is an inward rectifier potassium channel [12] that has two transmembrane [17] domains, M1 and M2, and constitutes the channel pore. The relative movements of M1 and M2 shape the gate that opens and closes the channel. As described above, SUR1 has two NBD whereas Kir6.2 does not seem to have a structurally obvious nucleotide-binding site. However, different studies have demonstrated that functional KATP channels devoid of the SUR1 subunit are sensitive to inhibition by ATP, but not by MgADP [18–20]. The sensitivity to ATP of Kir6.2 (Ki ∼100 ␮M) is lower when expressed in absence of SUR1, compared to when both subunits are co-expressed (Ki ∼10 ␮M). These data confirm that Kir6.2 contains a functional nucleotide bindingsite and that, in fact, nucleotides interact with both subunits. The currently accepted working hypothesis is that SUR1 mediates the stimulatory effects of MgADP and MgATP, whereas the inhibition of KATP channel is mediated by the binding of ATP or ADP to the Kir6.2 subunit. Moreover, SUR1 modulates the functional effects of ATP on Kir6.2.

3. The location of KATP channel in the ␤-cell Increased metabolic messengers as well as membrane permeable hormones such as steroids can exert their actions not only on KATP channels localized in the plasma membrane of pancreatic ␤-cells, but also on KATP channels present in intracellular organelles. Several studies have demonstrated the presence of KATP channels in secretory granules [21,22], which may be involved in lowering pH, promoting granule priming and secretion [23,24]. In addition, KATP channels are present in the mitochondria (mitoKATP ) where they take part in the regulation of calcium transport, volume, and membrane potential ( m), as well as in the release of proteins [25,26]. Several pharmacological studies have described the effect of mitoKATP channel modulators on ␤-cells [27,28]. A normal mitochondrial function ensures an adequate stimulus–secretion coupling and appropriate insulin release. It has been suggested that mitoKATP possess a similar structure as the plasma membrane KATP [29], but up to now, mitoKATP have not yet been precisely characterized in the pancreatic ␤cell. A functional KATP channel is also present in the nuclear envelope of pancreatic ␤-cells. Inhibition of these nuclear channels triggers nuclear calcium transients and induces phosphorylation of the transcription factor cAMP response element binding protein (CREB), triggering the expression of the immediate early gene c-myc [30]. Finally, KATP channels have been located in the endoplasmic reticulum (ER) and Golgi apparatus of different cells [19,31]. Some authors have suggested that they are involved in calcium movements in the sarcoplasmic reticulum (SR) in smooth muscle [32,33] but as yet their function remains unknown in these organelles.

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4. KATP channel regulation by physiological agents KATP channels are the link between glucose metabolism and electrical activity in pancreatic ␤-cells. A KATP channel shows a typical pattern of activity, oscillating between the open and closed states. Pharmacological modulators, like sulfonylureas, can regulate its activity by closing the channel and increasing the insulin secretion. Diazoxide has the opposite effect opening the channel and decreasing insulin release. Nevertheless, in physiological conditions, three agents are mainly responsible for KATP channel regulation: ATP/ADP ratio, phosphatidylinositol-4,5-bisphosphate (PIP2 ) and long-chain acyl-CoA esters (LC-CoAs) [34]. ATP production has been demonstrated to close the KATP channel via Kir6.2 subunits at high glucose concentrations [18–20,35]. However, the interaction of Mg-nucleotides (MgATP, MgADP) with SUR1 subunit leads to the activation of the channel. It has been suggested that the NBD2 of SUR1 subunit is responsible for the channel activation [14,18,36]. As a general rule, we can conclude that the channel activity in pancreatic ␤-cells is inhibited by nucleotide (ATP and ADP) binding to Kir6.2 and activated by Mg–nucleotide interaction with NBD2 of SUR1 subunit. PIP2 and LC-CoAs can likewise modulate the KATP channel; both of them can interact with the channel increasing the open probability and reducing its sensitivity to ATP [37–40]. It has been shown that the effects of PIP2 are mediated through the kir6.2 subunit [39]. In recent years the modulation of KATP channel activity by new physiological agents, like estrogens and xenoestrogens has been demonstrated.

5. How does estradiol modulate KATP channel in pancreatic ␤-cells? Estrogens are lipophylic hormones that are implicated in many actions in almost every cell type through diverse molecular mechanisms. The beneficial or detrimental effects of estrogens depend on their concentration and the specimen gender. It has also been demonstrated that E2 has cardioprotective effects because of their activation of mitoKATP in cardiomyocytes, protecting them against metabolic stress [41,42]. Estrogen therapy in postmenopausal women reduces cardiovascular mortality by 30% to 50% [43], but the consequences of hormone replacement therapy (HRT) are still controversial. It has been demonstrated that HRT increases the incidence of breast cancer and its effects depend on multiple factors such as the prescribed hormone, the doses and the route of administration [44,45]. As regards the endocrine pancreas, 17␤estradiol (E2) at physiological levels is involved in maintaining normal insulin sensitivity and ␤-cell function [46,47]. However, estrogen levels above or below the physiological range may cause insulin resistance and type 2 diabetes [46,48–50]. Estrogen actions are initiated at different locations, including the cell nucleus and the cell surface. Classically, nuclear estrogen effects have been attributed to the estrogen receptors (ERs), ER␣ and ER␤. The role of both receptor types in glucose homeostasis has been studied mainly in tissues other than the endocrine pancreas; for example, mice lacking ER␣ have hepatic insulin resistance and the expression of GLUT4 is decreased in white adipose tissue (WAT), diminishing glucose uptake [51,52]. Moreover, Barros et al. have shown that both ERs might modulate GLUT4 expression in smooth muscle of mice. In ER␤−/− mice GLUT4 expression was normal whereas in ER␣−/− ones GLUT4 was absent, indicating a repressive role of ER␤ [53,54]. In recent years, it has been demonstrated that ER␣ and ER␤ play important roles in the pancreatic ␤-cell [55,56]. Longterm exposure to physiological concentrations of E2 in synergy with stimulating glucose concentration increased insulin content,

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insulin mRNA levels and insulin release. There is evidence suggesting the involvement of ER␣ in these effects [55]. Recent studies have shown that some rapid effects of E2 in ␤-cells are mediated by ER␤ [57]. Stimulation of the ER␤ by its specific agonist DPN (2,3-bis (4hydroxyphenyl)-propionitrile), reduced KATP channel activity. This effect was proved to be absent in cells from ER␤ knockout mice. Moreover, PPT (propylpyrazole-triol), the specific agonist of ER␣, had no effect on the channel activity. These experiments demonstrated that the activation of ER␤ is required for the regulation of KATP channels by estrogens in pancreatic ␤-cells [47]. These studies completed the findings shown previously in which physiological concentrations of E2 (100 pM–1 nM) closed KATP channels enhancing the frequency of glucose-induced [Ca2+ ]i oscillations in a concentration-dependent manner. E2 rapidly decreased KATP channel activity: the initiation of the estradiol effects occurred from 30 s to 2 min after estrogen application. The authors demonstrated that the rapid modulation of [Ca2+ ]i was a nongenomic effect because pretreatment with actinomycin-D, an inhibitor of RNA synthesis, or cyclohexamide, an inhibitor of protein synthesis, did not prevent the effect of E2 [58]. The application of E2 has been shown to increase cGMP levels in pancreatic ␤-cells, while cAMP levels were unchanged [10]. The decline in channel activity was also produced by 8-Br-cGMP, a membrane permeable analogue of cGMP. The estrogen-induced decrease in channel activity was greatly reduced by a specific blocker of cGMP-dependent protein kinases (PKG), Rp-8-pCTcGMPS, indicating that a member of the PKG family was involved. The involvement of PKA was minor since Rp-cAMPS, a blocker of PKA, had a very small effect [9]. Finally, the lack of effect of two blockers of the soluble guanylate cyclase (sGC), LY83583 and ODQ, on E2 action indicated that this action may be mediated by a membrane guanylyl cyclase rather than the sGC [9,57]. The membrane GC family comprises several members, including GC-A and GC-B. These proteins produce cGMP upon activation. The atrial natriuretic peptide (ANP) and the brain natriuretic peptide (BNP) are both ligands for GC-A. Rodent islets of Langerhans express GC-A and respond to ANP by increasing cGMP [17,59]. The involvement of GC-A in the modulation of KATP activity by estrogens is suggested by the lack of effect of E2 in ␤-cells from GC-A KO mice. In addition, DPN did not modify the channel activity in these mice, suggesting that GC-A activation was downstream of ER␤ activation. However, the interaction between these two receptors remains unclear. Besides the ER␤ being involved in the rapid regulation of KATP channels in pancreatic ␤ cells by estrogens, additional mechanisms cannot be ruled out. On one hand, it has been demonstrated that the sulfonylurea receptor SUR1 can act as an estrogen-binding protein and potentiate E2-induced apoptosis in HEK cells [60]. However, E2 binds to SUR1 at supraphysiological concentrations (100 ␮M). On the other hand, Sarkar et al. reported that E2 has a direct effect on L-type Ca2+ channels in neurons [61], although this possibility has not yet been tested in pancreatic ␤-cells. It has been shown that estrogen can also modulate other KATP subunits. E2 stimulates the expression of the SUR2A subunit in a heart-derived cell line, but not that of the Kir6.2 one. This leads to an increase in the number of sarcolemmal KATP channels, which boosts the resistance to hypoxia-reoxigenation [62]. In recent years, the G protein-coupled GPR30/GPER has been proposed as a novel estrogen receptor [63–65]. Its presence in pancreatic ␤-cells has been demonstrated. It mediates rapid estrogen induced insulin release only at concentrations above the physiological range (5 ␮M) [66] as in the case of SUR1. Whether or not GPR30 is a novel estrogen receptor is still controversial. Recently, Balhuizen et al. have shown that the synthetic GPR30 ligand G-1 can mimic the effects of 17-␤ estradiol in pancreatic ␤-cells increasing insulin secretion [64]. However, other authors described that the

Fig. 1. . Rapid regulation of KATP channels by E2 in pancreatic ␤-cells. 17␤-estradiol regulates KATP channels in a cGMP-dependent manner. After binding to ER␤, E2 activates GC-A increasing the cGMP levels. Afterwards the KATP channels activity is decreased and this promotes membrane depolarization opening of the voltage dependent calcium channels (VDCC), inducing calcium signals that trigger insulin secretion. (Modified from [57]).

activities of GPR30 in response to estrogen and G-1 were due to its ability to induce ER-␣36 expression, an estrogen receptor variant [67]. Finally, Zhang et al. have recently described that E2 and STX (20 nM), a selective membrane estrogen receptor (mER) modulator, can enhance KATP channel activity in GnRH neurons at nanomolar concentrations (0.3–100 nM). The authors have concluded that this effect was mediated via a Gq-coupled mER other than GPR30 because ICI182, 780, which is an agonist of GPR30, had no effect on KATP activity [68]. If GPR30 or other new estrogen receptors can modulate KATP channels in pancreatic ␤-cells regulating insulin secretion remains still unclear and further research is necessary to clarify these effects.

6. Concluding remark The main function of pancreatic ␤-cells is the synthesis and secretion of insulin. KATP channels in pancreatic ␤-cells play an essential role in glucose-stimulated insulin secretion. It has been demonstrated that physiological concentrations of 17␤-estradiol, in synergy with stimulatory glucose concentrations, potentiate the insulin secretory response, and that both ER␣ and ER␤ are involved. Whereas ER␣ protects pancreatic ␤-cells from apoptosis induced by oxidative stress [69] and is responsible for increasing insulin content and insulin release after long term exposure to E2, ER␤ is involved in the rapid regulation of KATP channels and insulin release. The latter mechanism involves the GC-A induced increase of cGMP levels and the closing of the KATP channels [57] (Fig. 1). ER␣ and ER␤ may integrate information from 17␤-estradiol and different nutrients to provide the necessary insulin biosynthesis and release to compensate the enhanced insulin resistance promoted in diverse physiological states such as pregnancy, puberty and even, obesity.

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