Pharmacological and functional properties of voltagemi independent Ca2+ channels

Cell Calcium (1996) 19(4). 269-279 8 Pearson Professional Ltd 1996

Review

‘Pharmacological and functional properties of voltageindependent Ca*+ channels Emilio ClementP2, Jacopo Meldolesi2 ‘Department of Pharmacology, Faculty of Pharmacy, University of Reggio Calabria, Catanzaro, Italy *National Research Council, Cellular and Molecular Pharmacology Centre, B. Ceccarelli Centre, Department of Pharmacology, University of Milan0 and Dibit - San Raffaele Scientific Institute, Milano,

Italy

Summary During the last few years, considerable progress has taken place in our knowledge of the molecular and functional properties of the various voltage-independent Ca2+ channels. In addition to the ionotropic receptor-channels (ROCs), that are not discussed in the present review, these channels include the SMOCs, activated via second messengers or other transducing processes directly triggered by receptor activation; and the SOCCs, activated as a consequence of depletion of the rapidly exchanging Ca*+ stores in the cytoplasm. In parallel, a pharmacological approach to the study of these channels has been developed, based primarily on heterogeneous drugs already known for different biological effects, and subsequently recognized as voltage-independent Ca*+-channel blockers. From the systematic analysis of the effects of these drugs new information has emerged about SMOCs and SOCCs function. In addition, pharmacological blockade of these channels appears to have beneficial therapeutic effects in pathological conditions such as tumoral cell growth, inflammation and immunity. At the moment the field is rapidly evolving, with major developments expected in the years ahead.

INTRODUCTION

The existence at the cell surface of Ca*+ channels different from ionotropic receptors (ROCs, which will not be considered in the present review), and independent of voltage for their opening, working coordinately with the activation of receptors coupled to phosphatydylinositol 4,5-bisphosphate (PIP,) hydrolysis, has been widely recognized for many years. Soon after the discovery of inositol 1,4,5-t&phosphate (IP,), the [Caz+ll responses

Received Revised Accepted

8 December 23 January 23 January

1995 1996 1996

Correspondence to: Dr Emilio Clementi, Dip. Farmacologia, DIBIT, Scientific Institute San Raffaele, Via Olgettina 58, 20132 Milano, Italy Tel. +39 2 264 32770; Fax. +39 2 264 34813; e-mail [email protected]

triggered by activation of these receptors were found to include two components: an initial spike due to IP,induced Ca*+ release from intracellular stores and a sub sequent, slowly declining plateau sustained by the equilibrium between increased influx and the concomitant extrusion of the cation across the plasma membrane. For quite some time, however, the interest about influx remained moderate. The hypothesis of its regulation by a second messenger (from which the proposed nomenclature of second messenger-operated channels, SMOCs) [l], possibly IP, [Z] or its phosphorylated derivative, IP, [3], lost impact progressively and was substituted by that of a G protein, distinct from that involved in the coupling of the receptor to phospholipase C, sustaining the activation of Ca2+ channels by an independent coupling [4]. Concomitantly, the ‘capacitative influx’, initially attributed to a direct Ca2+-permeable pathway connecting IP,sensitive storage organelles to the plasmalemma [5], was recognized to be based on a functional, and not a physical interactions between the two structures [6]. It was, 269

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however, with the introduction in CaZ+research of a new class of drugs, thapsigargin and the other blockers of intracellular sarcoplasmic-endoplasmic reticulum Ca*+ ATPases (SERCA) [7-lo], i.e. drugs that induce discharge of the intracellular, rapidly-exchanging Ca2+ stores via a mechanism not involving receptors [7-91, that unexpected aspects of CaZ+influx regulation were revealed. In particular, capacitative influx was discovered to be activated by the simple emptying of the intracellular Ca*+ stores. The subsequent electrophysiological characterization of the current underlying capacitative influx, first in mast cells and lymphocytes [ 11,121, and then in many other cell types (Hoth M., personal communication), led to its definition as I,,, (Ca*+ release-activated current). Altogether, the channels controlled by the filling state of the stores can be referred to as store-operated Ca2+channels (SOCCs) [ 12- 141. A complete overview of the literature concerning the physiology of SMOC and SOCC channels is beyond the purpose of the present report. For this we address the reader to other recent reviews [ 13,15, 161. Here we will focus on aspects that, although relevant for channel function, have not been comprehensively discussed yet. In particular, the information on drug action on these channels is still scattered throughout the literature, not integrated in an organic scenario. Specific attention will, therefore, be devoted to the pharmacology of voltage-independent channels and to the information about channel functioning arising therefrom. SMOC

CHANNELS

The SMOC family includes the channels opened as a direct consequence of receptor activation. These channels, although expressed primarily by excitable cells [4,9,17] are found also in non-excitable cells [ 18-201. Indication of their existence as independent entities has been obtained primarily by the Fura- [Ca*+], measurement applied to a variety of cells analyzed in a number of experimental conditions (see e.g. [8,9,17,18]). Among the findings of these studies are the increased Ca2+ influx observed in cells already fully depleted in their stores by thapsigargin pretreatment, when exposed to receptor activation; and the quicker activation of the influx sustained by SMOCs with respect to SOCCs [9,18]. Consistent with the existence of distinct SMOC and SOCC channels are also the results of pharmacological studies discussed below in this review. Altogether, SMOCs appear to comprise an apparently heterogeneous family of channels, regulated by a variety of second messengers: in addition to IP,, IP4 and G proteins (seeabove), also cGMP [2 I-231, protein kinase C [19] and Ca2+ itself [20,24] have been reported to be involved. Most of these channels appear permeable to Ba2+ [20,24,25]; many [17,18,24,26,27], but not all [9,20], to Mn2+. Opening of SMOC channels has Cell Calcium

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been described for a number of receptor agonists acting on G protein-coupled receptors, e.g. carbachol [4,9], ATP [28] histamine [ 171, fMLP [ 18,261. In addition, recent evidence suggests SMOCs to be activated also when cells are stimulated with cytokines [ 191 and growth factors [27,29]. At the moment, any classification of these heterogeneous channels would be inevitably inadequate, since many of their properties have not been defined with certainty yet, and since important aspects remain largely unexplored. For this reason we feel it premature to propose new nomenclatures and will continue to refer to them as SMOCs. SOCC

CHANNELS

SOCC channels predominate in non-excitable cells and are present also in many (although probably not in all) excitable cells. Electrophysiological studies in lymphocytes and mast cells revealed the channel sustaining I,,,, to be characterized by very high Ca2+ specificity, with reversal potential above +5O mV, and by extremely small (< 100 fS) unitary conductance [ 11,121. Consequently, the cells exhibiting appreciable I,,, are believed to express high numbers of these channels. In other cell systems investigated by the Fura- technique, however, the SOCC channels have been reported to be permeable to different cations, including Mn*+ [9,18,26,27] and Ba2+ [ 18,301. These findings suggest that the channels responsible for SOCC influx are heterogeneous. The unitary conductance and other properties of these non-I,,, SOCCs have not been established with certainty yet. SOCCs activation is still a matter of debate. Electrophysiology revealed that these channels are activated by store depletion even when investigated in a detached, inside-out patch crammed back into the cytoplasm of the analyzed cell [31]. This result can be explained only by the existence of a specific, diffusible messenger released into the cytosol, moving on a direction opposite to that of IP,, and responsible for signalling the empty state of the stores to the plasma membrane. The nature of this messenger remains at least partially mysterious. Two and a half years ago Randriamampita and Tsien described an extract (referred to as CIF, Ca*+ influx factor) containing a phosphorylated, low molecular weight component, isolated from stimulated cells and capable of activating influx even when administered from outside the cell [32]. Recent studies revealed, however, that Ca*+ influx activated by the extract is due to multiple and heterogeneous components, with little specificity for Ca2+ and with reversal potential around 0 mV (instead of +50 mV as ICRAC)(see [ 141). Further investigation of the extract has revealed the existence of component(s), present in low concentration, which appear(s) capable of activating I,,, only when administered inside the cell 1331. Whether or 0 Pearson

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Pharmacological and functional properties of voltage-independent Caz’ channels

not these components are chemically identical to the active principle of CIF is still a matter of debate. Altogether, the present state of CIF and related molecules is, therefore, unclear. Several other mechanisms have been proposed to account for SOCC activation. Direct coupling of these surface channels to IP, receptors [3] appears unlikely because images of close contact between endoplasmic reticulum (ER) cisternae and the plasmalemma are rarely obtained in most cell types. Involvement of small GTP binding proteins was suggested by the observation that injection of GTP@ inhibits SOCCs in rat basophilic leukemia cells [34], mouse lacrimal acinar cells 1351and H~60 granulocytes [36]. In platelets and human fibroblasts, a tyrosine phosphorylation step was suggested to be critical for SOCC activation since influx inhibition was observed after cell treatment with tyrosine kinase blockers [37,38]. In various experimental models, a role for protein phosphatases, working to relieve an inhibition of channel opening by serine-threonine kinases, was suggested by the inhibitory effect observed both with the protein phosphatase blocking drug, okadaic acid [3,9,40], and the protein kinase C activators, the phorbol esters [41]. Another mechanism of regulation, that at the moment appears to be gaining momentum in a variety of different cell systems including pancreatic acinar cells (142,431 but see [44]), mouse fibroblasts [27], human epithelial cells [30] and platelets [45], is the increase of cytosolic cGMP levels with subsequent activation of the soluble cGMPdependent protein kinase. In many of the experiments, the increased cGMP levels were obtained as a consequence of cell stimulation with nitric oxide (NO) donors [27,30,43,45,46]. These findings suggest that an important role in SOCC activation could be played by the Ca2+dependent, constitutive NO synthesizing enzyme, NO synthase (NOS). Indeed, when NOS or guanylyl cyclase activity were inhibited, a parallel, partial reduction in SOCC influx was observed 12743,461. The sequence of events occurring in NOS-competent cells could therefore include: activation of membrane receptors, followed by release of Ca2+from intracellular stores; generation of NO (by activation of the Ca2+-dependent NOS); and finally activation of Ca2+ influx by the gaseous messenger leading to the rapid refilling of the stores. At very high levels of cGMP, however, the stimulatory effect has been shown to switch to inhibition 1431,a property that could work as a safety mechanism. At variance with this model, it must be pointed out that, in platelets, both NO and cGMP have been reported to exert an overall inhibitory effect on SOCC influx [45,47]. Due to the high diffusibility of NO across cell membranes, the involvement of the NOcGMP pathway raises the possibility of complex, transcellular regulation of SOCC activation, at least in tissues where close contacts exist among cells. 0 Pearson

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The multiple mechanisms of SOCC activation and function described here suggest the existence, in various cell types, of channels differing not only in functional properties but also in molecular structure. An approach that is expected to contribute to progress in the field is therefore molecular biology. At present, attention is focused on two channels, named w (which stands for transient receptor potential) and &L$ (trplike). Both were cloned a few years ago from the Drosophikz eye, where they encode for putative light-sensitive channel subunits (see [48] for review). Of these, only tv has the high Ca2+ selectivity and low conductance properties expected for an I cRAc-type channel. When ty was expressed in insect cells, its functioning appeared to be regulated by the state of the stores 1491, a property maintained by a chimera of t$ in which the C terminal domain, located in the cytoplasm, was replaced with that of @ [50]. The C terminal domain of trp is particularly long, over 400 amino acids. The hypothesis was thus raised of a direct interaction of this domain of the channel with ER membranes. However, the mammalian homologues of +J so far identified were found not to share the long C terminal tail of the Drosophila channel [14,5 1,521. Therefore, a direct connection to the ER membrane by the channels inserted in the plasmalemma appears unlikely, at least in mammals. If indeed mammalian trp channels belong to the SOCC family, the field is expected to undergo rapid progress, with clarification of at least some of the mysteries that still remain.

PHARMACOLOGY Ca*+ CHANNELS

OF VOLTAGE-INDEPENDENT

Until recently, no specific interest existed for SMOC and SOCC pharmacology. Initial results were therefore obtained either by chance or as the fall-out of studies in different fields. Nonetheless, various drugs have proven to inhibit cationic influx through these channels. Although performed with various methodologies (45Ca2+uptake, Fura- and patch-clamp techniques), and although being often far from exhaustive, these pharmacological studies have yielded new, interesting information on the function and properties of the channels themselves. The SOCC inhibitors that have been already characterized are listed in Table 1. In many studies, the inhibitory effects on SMOCs and voltage-operated Ca2+ channels (VOCCs), as well as the ability of releasing Ca2+ from intracellular stores were also investigated, often however not in enough detail to yield accurate potency estimations. In the table, therefore, IC,, values are reported only for the effects on SOCCs, while for the other Ca2+ channels, as well as for Ca2+ release, only the presence/ absence of the effect is indicated. Cell Calcium (1996)

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Table 1 Drugs acting on voltage-independent CaZ+ channels: blockade of SOCCs (with IC,,), of VOCCs and SMOCs; stimulation of Ca2’ release from intracellular rapidly exchanging stores. Pharmacological

classes

soccs

voccs

Ca2+ release

SMOCs

I&, W’4 Ca*+ antagonists SK&F96365 SC38249’ LOEQ08 LU52396 L-651,582 tetrandrine

3;4;14-46 13 0.04;50;5.4-9.5 2 1.2 20

Cvtochrome P450 inhibitors a-naphthoflavone econazole* miconazole’ clotrimazole’ ketoconazole* RS-14647* RS-73520*

[53-5$657] [54;56;57]

WI

[55,114]

+ + +

+

+;+ [541

+

1581

+

v141 [59;60]

WI

+I-

[751

10 0.2; 0.8; 11 0.5;1-4 2; 2-l 9 15; 22-80 0.3 0.2

[55,68;56;71] [55,68;142] [55,68,111;142] [55,68;142] [551 [551

+ + + +In.d. n.d.

12 4

[55,68,143] [68,92,93,143]

+ln.d.

1751

13.5 23

[56,145]

+ n.d. n.d. n.d.

[I451

-I+

P511

Lipooxygenase inhibitors nor-dihydroguaiaretic acid eicosatetraynoic acid Cyclooxygenase inhibitors tenidap NPPB NPPA niflumic acid flufenamic acid

190

150 33

if461 [146,148] [I461 u501

:;z; ;:z;

[53,54,80;25]

-I+;-

[9,140]

-

n.d. -I+ + + +l+;+;+!+

n.d.

WI

ii-

[114] 1601

+

[751

nd. -;+/-I+ + n.d. n.d. n.d.

[23,75,80,141;25] [75;141]

+ n.d. n.d.

+ + n.d. + n.d. n.d. +

[75,80]

-

1921

[I471

[150-1521

-;+I+ln.d. n.d. + +

[25,53,62;117]

191 1281 [1141 [581

[25,142;62] [621 ml

[92,144] [92;93]

[I451

11491 11491

SOCC inhibitors are grouped according to their originally described effect. Many of them could have been classified otherwise: e.g. the antimycotic drugs econazole, miconazole, ketoconazole and clotrimazole are also known as VOCC blockers, cyclooxygenase and lypooxygenase inhibitors; NDGA and ETYA inhibit also cytochrome P450 and cyclooxygenase activity. The asterisks indicate imidazole derivatives, - indicates no effect. -/+; +/-; +; indicate the dose required for the effect to be distinctly higher, slightly higher or equal to that reported for SOCC inhibition. When investigated, the ligand-gated channels (nicotinic and PZwreceptors) were unaffected by the drugs presented here (not shown).

The first general observation that emerges from the reported data is the high degree of variability reported for a single drug in similar studies, carried out however in different cell types. This variability is a further evi: dence of heterogeneity within the SOCC family. The second observation is that no drug appears specific for either the SOCCs or the SMOCs, but the channels of the two classes are inhibited in parallel by all drugs tested, although sometimes with remarkably different potency. In the rest of this chapter the drugs listed in Table 1 will be discussed systematically. Ca*+ antagonists

Among the drugs specifically designed to work as Ca2+ antagonists, SK&F96365, L-65 1,582 and tetrandrine were reported to inhibit with equal potency SOCCs, VOCCs and SMOCs 153-611; SC38249 to be a more potent inhibitor of SMOCs [9], and LU52396 of SOCCs [28]. The latter drug, however, is not SOCC-specific since even lower concentrations were found to inhibit VOCCs Cell Calcium (1996) 19(4), 269-279

(Sciorati C. and Clementi E., unpublished results). Some of these drugs were reported to induce Ca2+ release either by inhibition of SERCA activity (SK&F96365 and LU52396) 128,621 or by other, yet unidentified, mechanisms (tetrandrine) [58]. Finally, both tetrandrine [63] and SK&F96365 [64] have been shown to interfere with K+ channels in many cell systems. The latter drug (as well as tenidap and econazole, see below) inhibits also CAMPactivated Cl- current in mast cells, with an IC,, in the same range as inhibition of the SOCC activity 1561. Among Ca2+ channel antagonists, LOE908 appears to be of special interest since, when SOCCs and VOCCs were investigated in parallel, the observed I&s were markedly different: 40 nM and 28 FM, respectively 1651. The effects of this compound on SMOC channels and Ca2+ release have not been investigated yet. inhibitors

of cytochrome

P450

A peculiar aspect of the pharmacology of voltage-independent channels is that heterogeneous drugs, previ0 Pearson Professional Ltd 1996

Pharmacological and functional properties of voltage-independent C& channels

ously believed to act specifically on different biological functions of the cells, were later found to affect also SOCC (and SMOC) function. This raises the question about the mechanisms of action of these drugs, and whether, and to what extent, their known biological effects take part in voltage-independent channel inhibition. Among the first recognized SOCC/SMOC inhibitors are imidazole antimycotic drugs known to inhibit the activity of cytochrome P450, the major component of the electron transport chain of ER membranes [66,67]. An ensuing series of studies (concentrated on SOCC channels) was aimed to establish whether or not cytochrome P450 does play a role in channel inhibition. 1n favour of an involvement of the cytochrome (and metabolites) are the observations that, in rat thymocytes, the groups of cytochrome P450 inhibitors able to inhibit SOCCs (CO; econazole, miconazole, ketoconazole, clotrimazole; anaphthoflavone) 1681 are structurally unrelated; and that, in human neutrophils, the kinetics of inhibition of SOCC influx by fast refilling of the stores and by econazole are in the same range [69]. More importantly, in human and bovine endothelial cells, the inhibitory effect of various cytochrome P450 inhibitors on SOCC functioning was prevented in the presence of the P450 monooxygenase product, 5,6-epoxyeicosatrienoic acid [70]. In the meantime, however, experimental evidence that cytochrome P450 is not involved in channel regulation accumulated in the literature. For example, administration of CO to platelets, while inducing marked cytochrome P450 inhibition, was found to have no inhibitory effect on SOCC influx [71]. Moreover, two strictly related imidazole derivatives, RS-14647 and 73520, the first designed as a strong, the second as a weak, cytochrome P450 inhibitor, exhibited similar potency in SOCC inhibition [55]. Taken together with the lack of specificity of cytochrome P450 inhibitors for ion channels in general (not only those for Ca2+ but also those permeable to Cl- and K+, see below), these results suggest that inhibition of cytochrome P450 has little, if anything, to do with the actual mechanism of SOCC blockade. It should be acknowledged, however, that all the above experiments were performed in only a few, diverse cell models: since SOCCs appear heterogeneous, the existence of both cytochrome P450-dependent and independent channels cannot be excluded. In the case of antimycotic drugs, inhibition of cytochrome P450 is not the only possible mechanism for SOCC blockade. Econazole and miconazole have been shown to inhibit agonist-evoked protein-tyrosine phosphorylation [72], an event already shown to inhibit SOCC activity (see above). In addition, both drugs, as well as clotrimazole, are potent inhibitors of constitutive and inducible NOS isozyme activity, presumably via interaction with the Ca2+-calmodulin complex or with the haem moiety of NOS themselves [73,74]. 0 Pearson

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The drawbacks of the cytochrome P450 inhibitory drugs in the investigation of voltage-independent Ca2+ channels go far beyond their poorly defined mechanism(s) of action. These drugs, in fact, not only do not discriminate between SMOCs and SOCCs, but also induce Ca2+ release via SERCA blockade 1621. Moreover, they inhibit VOCCs (with a similar IC,,) [75] and K+ channels in a variety of cell types including human erythrocytes and myocytes, rat thymocytes and Ehrlich ascites tumour cells [76-781. Additional effects that have been reported include cyclooxygenase and lipooxygenase inhibition [79,80], induction of mRNA for hepatic cytochrome P450 isozymes [81,82], and blockade of CAMP-activated Clchannels [56]. Inhibitors of cyclooxygenase lipooxygenase activity

and

Among drugs of miscellaneous structure that have been proposed to exert inhibitory effects on voltage-independent channels are fenamates and other cyclooxygenase and/or lipooxygenase inhibitors. As with the cytochrome ~450 inhibitors discussed above, the mechanism of action of these drugs is still undefined and the multiplicity of biological effects is considerable. 4-nitro-2(3-phenylpropylamino)benzoate (NPPB), n-phenylanthran- ilic acid (NPPA), flufenamic and niflumic acids are in fact well known Cl- channel blockers [83-861; flufenamic and niflumic acids potentiate K+ channels [87,88], and variously affect cationic influx through neuronal nicotinic receptors 1891. In addition, many effects of cyclooxygenase inhibitors on Ca2+ homeostasis are complex and apparently non-specific (seeTable 1). A similar unspecificity of effects can be seen with the lipooxygenase blockers, 5,8,ll,lCeicosatetraynoic acid (ETYA) and nor-dihydroguaiaretic acid (NDGA). Both these drugs are cytochrome P450 inhibitors [go], while ETYA is also a false substrate for cyclooxygenase and an inhibitor of cardiac K+ channels 1911. The effects of these drugs on Caz+ channels appear non-specific: NDGA inhibits SMOCs, VOCCs and SOCCs with similar IC50 (see Table 1). ETYA appears more selective since the IC,, for SMOC inhibition is lofold higher than that required for SOCC inhibition [92]. This drug, which has not been tested yet for VOCC inhibition, can however induce Ca2+ release from intracellular stores 1931. Despite the lack of specificity of these drugs, some of their properties have revealed important aspects of channel regulation. The first concerns the possibility that their inhibitory effects on SMOCs and SOCCs arise from their interference with the metabolism of arachidonic acid, a mechanism documented, at least in part, for SMOCs in GH, cells, by analogy with the reported facilitatory action of the acidic second messenger on VOCCs Cell Calcium

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[94,95]. An intriguing observation is that fenamates, NPPB, ETYA and NDGA, all uncouplers of the mitochondrial respiratory chain [96-981, induce disruption of the cristae [99] and impair mitochondrial functioning, in some cases resulting in destruction and disappearance of the organelles [ 1001. These observations reinforce a recent report demonstrating a critical dependence of SOCC activation upon the ATP/ADP ratio in several cell systems, including PC12, HeLa, Jurkat, endothelial cells and lymphocytes [loll. At least two different (but not necessarily alternative) interpretations of these findings can be suggested: a direct facilitatory effect of ATP on SOCC activity, as already described for VOCCs [ 1021 Cl[ 1031 and K+ [ 1041 channels; and/or the involvement of protein kinases in SOCC functioning, as already mentioned above. Another mechanism that could play some role in SOCC inhibition is acidification of the cytosol, with subsequent impairment of pH-dependent cell activities. In fact, it has been demonstrated that the K+/H+ ionophore, nigericin, decreases the SOCC-mediated Ca2+influx [93]. Both ETYA and tenidap induce acidification of the cytosol, though via different mechanisms [93,105]: the possibility, therefore, exists that part of their inhibitory effect on SOCC is due to the latter mechanism. A final mechanism of action for ETYA (and NDGA) might be the decrease in cGMP levels, due to inhibition of guanylyl cyclase activity [ 106,107].

THERAPEUTIC INDEPENDENT

USE OF VOLTAGE= Ca*+ CHANNEL BLOCKERS

Recently, interest about the voltage-independent channel blocker drugs has unexpectedly increased because of the recognized inhibitory effect of some of them on tumoral growth. The idea that Ca2+has a role in the control of cell growth is by no means new. Previous studies had shown in fact that stable expression of truncated IP, receptors induces inhibition of cell growth, with suppression of EGF-induced transformation in NIH 3T3 fibroblasts [IOS], while virally transformed cells exhibiting a modified regulation of Ca2+ homeostasis [log] were shown to depend on an intact Ca2+ influx system for their proliferation [ 1 lo]. Recently, clotrimazole was reported to inhibit cell proliferation in both cultured cells and intact nude mice [l 111, whereas its analogue econazole was poorly effective [l 111. Since clotrimazole induces not only Ca2+ influx inhibition but also Ca2+ release, while econazole does not (cited in [ 11 l]), the block of tumoral growth was suggested to be induced by a comprehensive alteration of Ca2+ homeostasis rather than by influx inhibition alone. The concentrations of clotrimazole active on cell growth are in the low FM range, the same employed for Cell Calcium

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years in antimycotic therapy, with few toxic side-effects [l 111. This observation encouraged the investigation of the drug in tumor therapy which is now proceeding also at the clinical level. Among the other Ca2+ channel blockers, tetrandrine [112], L-651,582 [113,114], SK&F96360 [115-1181 and SC38249 [ 1191 have all been reported to inhibit cell proliferation, essentially by virtue of their action as Ca*+ channel blockers. One of these drugs, L-651,582, has been successfully employed in cancer therapy of experimental models, both in vitro and in vivo, including human cancer xenografts [ 120- 1221. Currently, a phase 1 study on ovarian cancer is in progress at the US National Cancer Institute [ 1231. Other fields in which voltage-independent Ca*+ channel blockers can have therapeutic implications are inflammation and immunity. The role of Ca2+ influx through I,,,, channels appears crucial in the control of T cell activation and proliferation. In the case of a patient suffering from a primary immunodeficiency, the molecular defect associated with defective T cell proliferation was in fact demonstrated to be the lack of functional SOCC channels [124]. Moreover, SK&F96365 has been shown to inhibit IL-2 synthesis [117], while tenidap inhibits synthesis and secretion of IL-la, IL-l B, IL-6 and TNFa in human and mouse mononuclear cells [ 125-1281. These effects of tenidap appear independent of its cyclooxygenase inhibitory activity and dependent upon the impairment of Ca2+ influx [ 1251. The action of tenidap on human chondrocytes and synovial fibroblasts [ 129-13 11, its inhibition of collagenase release by neutrophils [ 1321, as well as its overall protection of cartilage integrity [ 1331, all effects more prominent than those observed with other non-steroidal anti-inflammatory drugs (NSAIDs), have fostered its use in rheumatic diseases. The success of this approach in the therapy of rheumatoid arthritis and osteoarthritis is demonstrated by several clinical trials (reviewed in [ 1341). The beneficial effects of tenidap appear similar to those observed with the combination of the so-called ‘disease-modifying’ (or ‘second line’) antirheumatic agents plus NSAIDs [ 134, 1351, suggesting tenidap as a drug of primary importance in the treatment of such disorders. A final perspective for at least some of the voltageindependent Ca2+ channel blockers is their potential use in calcium metabolism disfunctions, primitive or associated with other diseases, such as sarcoidosis, tuberculosis and various endocrinological disorders. In this respect a pivotal role could be played by ketoconazole, which has been used with success in the control of hypercalcemia associated with both sarcoidosis and tuberculosis [ 136- 1381. The overall impact of voltage-independent channel blockers in such therapies, however, is at present still low. 0 Pearson

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CONCLUSIONS

Knowledge about voltage-independent channels of the plasmalemma has accumulated slowly during the past several years. Recently, however, the pace has become faster and thus the present stage is of considerable interest. Especially in the case of SOCCs, rapid developments are expected in the next months based on a few, well established acquisitions: the existence of a reverse signalling system, from intracellular stores to the plasmalemma, which is on its way to characterization; the molecular and functional studies of @, I,,, and homologous channels. The recognition of the unexpected potential of at least some voltage-independent channel blockers against tumoral growth, in the therapy of metabolic disorders and as immunosuppressants has greatly increased the appeal of the field, from the intellectual and also from the practical point of view. The development of new panels of drugs, well characterized in their effects on the various Ca2+events taking place within the cell, appears at the moment more than worth doing. Together with the analyses of recently identified cell mutants defective in SOCC influx [ 1391, the development of new drugs could ultimately play significant roles in Ca2+studies and at the same time contribute to the clarification of fields in which the involvement of channels still remained obscure.

8.

9.

10. 11. 12 13 14. 15 16 17 18

ACKNOWLEDGEMENTS

The original work included in this review was supported in part by grants from AIRC, Italian Association of Cancer Research, and from the Target Project ACRO of the Italian National Research Council. We thank E.K. Rooney for fruitful discussion and suggestions. REFERENCES 1. Meldolesi J., Pozzan T. Pathways of Ca2+ influx at the plasma membrane: voltage-, receptor-, and second messenger-operated channels. Exp Cell Res 1987; 171: 271-283. 2. Kuno M., Gardner P. Ion channels activated by inositol 1,4,5trisphosphate in plasma membrane of human T-lymphocytes. Nature 1987; 326: 301-304. 3. Irvine R.F. Inositol phosphates and Ca*+ entry: toward a proliferation or a simplification?. FASEBJ 1992; 6: 3085-3091. 4. Felder C.C., Poulter M.O., Wess J. Muscarinic receptor-operated CaZ+influx in transfected fibroblast cells is independent of inositol phosphates and release of intracellular CaZ+.Proc Natl Acad Sci USA 1992; 89: 509-513. 5. Putney Jr J.W. A model for receptor-regulated calcium entry. Cell Calcium 1986; 7: 1-12. 6. Putney Jr J.W. Capacitative calcium entry revisited. Cell Calcium 1990; 11: 61 l-624. 7 Jackson T.R., Patterson S.I., Thastrup O., Hanley M.R. A novel tumour promoter, thapsigargin, transiently increases

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(1996)

19(4),

269-279