Elsevier

Cell Calcium

Volume 42, Issues 4–5, October–November 2007, Pages 397-408
Cell Calcium

L-type calcium channels in adrenal chromaffin cells: Role in pace-making and secretion

https://doi.org/10.1016/j.ceca.2007.04.015Get rights and content

Abstract

Voltage-gated L-type (Cav1.2 and Cav1.3) channels are widely expressed in cardiovascular tissues and represent the critical drug-target for the treatment of several cardiovascular diseases. The two isoforms are also abundantly expressed in neuronal and neuroendocrine tissues. In the brain, Cav1.2 and Cav1.3 channels control synaptic plasticity, somatic activity, neuronal differentiation and brain aging. In neuroendocrine cells, they are involved in the genesis of action potential generation, bursting activity and hormone secretion.

Recent studies have shown that Cav1.2 and Cav1.3 are also expressed in chromaffin cells but their functional role has not yet been identified despite that L-type channels possess interesting characteristics, which confer them an important role in the control of catecholamine secretion during action potentials stimulation. In intact rat adrenal glands L-type channels are responsible for adrenaline and noradrenaline release following splanchnic nerve stimulation or nicotinic receptor activation. L-type channels can be either up- or down-modulated by membrane autoreceptors following distinct second messenger pathways. L-type channels are tightly coupled to BK channels and activate at relatively low-voltages. In this way they contribute to the action potential hyperpolarization and to the pace-maker current controlling action potential firings. L-type channels are shown also to regulate the fast secretion of the immediate readily releasable pool of vesicles with the same Ca2+-efficiency of other voltage-gated Ca2+ channels. In mouse adrenal slices, repeated action potential-like stimulations drive L-type channels to a state of enhanced stimulus-secretion efficiency regulated by β-adrenergic receptors.

Here we will review all these novel findings and discuss the possible implication for a specific role of L-type channels in the control of chromaffin cells activity.

Introduction

Voltage-gated L-type Ca2+ channels are widely expressed in many tissues and control a number of Ca2+-dependent responses in electrically excitable cells. They include several subtypes containing the pore-forming α1S, α1C, α1D and α1F subunits (Cav1.1, Cav1.2, Cav1.3 and Cav1.4) with different structure–function characteristics but common blockers: dihydropyridines (DHPs), phenylalkylamines, benzothiazepines [1]. Members of the L-type channel family activate upon membrane depolarization and represent one of the central pathways by which intracellular Ca2+ can be raised in neuronal and neuroendocrine cells [2], [3]. Elevation of intracellular Ca2+ represents the triggering event of hormone secretion and cell differentiation [4], [5], and thus the right characterization of L-type channels functioning and their modulation helps understanding key issues of neuroendocrine cells activity and neuronal functioning.

L-type channels possess several properties that are important for the control of neuroendocrine cell activity. The first is their high density of expression and main role in the control of hormone secretion in a variety of cells. L-type channels have indeed wide control of insulin release in pancreatic β-cells [6], [7], pituitary glands [8] and catecholamine in a number of chromaffin cell species [9], [10], [11]. In addition to this, their density can be either up- or down-regulated by various stimuli, including: hypoxia [12], growth factors [13], hormones [14] and neurotransmitters [15]. The second property of L-type channels is that their gating can be effectively inhibited or potentiated by neurotransmitters coupled to membrane receptors (see [16], [17] for reviews). Among the many modulatory pathways, two appear of particular interest for neuroendocrine cells because of their autocrine nature: the membrane-delimited G protein-dependent inhibition and the remote cAMP/PKA-mediated potentiation [16], [17]. In chromaffin cells, both pathways are activated by autoreleased neurotransmitter molecules and produce opposing effects of comparable entity [18]. A third property of L-type channels of particular interest is their low-threshold of activation with respect to the other high-threshold channels (N, P/Q, R), which is remarkably low for the Cav1.3 isoform [19], conferring to it the ability of pace-making cells [20]. This is true also in chromaffin cells that express both Cav1.2 and Cav1.3 [21], [22], [23], [24] and, thus, an open question is how much the two channels contribute to the genesis of action potential firings and how much the different gating modulations induced by membrane receptors reflect a different action on these two channel types. A final interesting point worth being underlined is the tight coupling between Ca2+-activated K+ channels and L-type Ca2+ channels [25], [26], which condition the shaping of action potential and the frequency of action potential firing. Strict co-localization of BK and L-type channels as postulated for the rat chromaffin cells (RCCs) implies a further direct control of L-type channels on Ca2+ influx through other voltage-gated Ca2+ channels.

In our view these peculiar properties of L-type channels are so strategic for the activity of chromaffin cells that their full understanding will help solving critical issues concerning the physiology and pharmacology of catecholamine release during extreme electrical stimulation of the adrenal gland, as it occurs during basal or stressful body conditions. This review aims at clarifying some of the peculiarities that L-type channels possess and that are linked to the regulation of intracellular Ca2+ required for triggering vesicle exocytosis and catecholamine release. The recent observations that Ca2+ entry through voltage-gated Ca2+ channels can be tightly linked to the mitochondria and endoplasmic reticulum Ca2+ buffering system [27], [28] may be one of the new arguments that we have to face in the near future (see [11] for e review).

Section snippets

The direct and remote L-type channel modulation in RCCs

L-type channel modulation is largely heterogeneous and covers a broad spectrum of molecular mechanisms. A major subdivision should include the signaling pathways that are either voltage-dependent or voltage-independent. Among the first class should be mentioned: (1) the voltage-dependent facilitation producing L-type current increases following strong and long lasting pre-pulses described in cardiac, neuronal and neuroendocrine cells [29], [30], [31] and, (2) the voltage-dependent and

Two functionally active L-type channels in chromaffin cells?

The schematic model of Fig. 1C assumes arbitrarily that the two opposing mechanisms mediated by β1 and β2-ARs converge on the same L-type channel but the alternative possibility that the two pathways target two distinct L-type channel isoforms cannot be excluded. RCCs and BCCs, are shown to express Cav1.2 and Cav1.3 channels [22], [23], [24] and thus the possibility that the direct inhibition by β2-AR acts on Cav1.3 and the remote potentiation mediated by β1-AR targets Cav1.2 (Fig. 1D) is an

Evidence for a “low-threshold” L-type channel controlling RCCs excitability

Cultured RCCs express both Cav1.2 and Cav1.3 isoforms but a selective separation of their biophysical properties has not yet been possible. There are however some clear indications that either one or both channels play a critical role in cell excitability, action potential firing and catecholamine secretion. The first evidence is illustrated in Fig. 2 and is related to the capability of L-type currents to activate at relatively low voltages (−60 to −40 mV) and contribute up to 10% of the total Ca

L-type channels control the firing frequency of spontaneously active RCCs

BK currents play a crucial role in shaping the action potential repolarization phase and tuning the recruitment of Na+ and Ca2+ channels that are responsible for the subsequent slow depolarization phase of spontaneously firing cells [25], [60]. It is thus reasonable to believe that the tight coupling of L-type to BK channels is likely involved in the control of pace-maker activity in RCCs. Since RCCs express L-type channels that are already open at resting potentials (10% at −50 mV in 2 mM Ca2+) (

L-type channels and fast exocytosis in chromaffin cells

As discussed in recent reviews [11], [23], [71], [72] chromaffin cells express different densities of high-voltage and low-voltage-activated Ca2+ channels. Their coexistence at the plasma membrane raises the question of whether all these channel types participate to the control of exocytosis and how their density of expression and gating properties affect their contribution. In addition, the proportion of various Ca2+ channels varies widely between animal species and, thus, catecholamine

Ca2+ channels-secretion coupling in chromaffin cells

A generally accepted model of Ca2+ channels and vesicle distribution in chromaffin cells assumes that vesicles are colocalized in microscopic domains distributed all over the cell with Ca2+ channels uniformly distributed [42] and located at an average distance of 200 nm, i.e., at a distance comparable to the vesicle size [91], (Klinghauf-Neher model). According to this model all Ca2+ channel types are more or less uniformly distributed at the secretory sites and contribute to secretion

Conclusions

The importance of L-type channels in the control of chromaffin cell excitability and catecholamine secretion is now well documented and increases progressively meanwhile new experiments become available. The contribution of L-type channels appears critical in the control of action potentials frequency in spontaneously firing cells and this may result in an even more critical role in the overall control of catecholamine secretion. L-type channels are also effectively modulated by the same

Acknowledgments

This work was supported by the Italian MIUR (grants COFIN No. 2005054435 to EC), the Regione Piemonte (grants No. A28-2005 to VC and No. D14-2005 to EC), the San Paolo IMI Foundation (grant to the NIS Center of Excellence), the European Research Training Network CavNET and by a Ramon y Cajal contract and grant 2004/07998 to JM H-G.

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    1

    Present address: Department of Experimental Medicine, Viale Benedetto XV 3, 16132 Genova, Italy.

    2

    Present address: Department of Pharmacology & Therapeutics, Universidad Autónoma de Madrid, Av. Arzobispo Morcillo 4, 28029 Madrid, Spain.

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