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Ca v 1.3 Channels as Key Regulators of Neuron-Like Firings and Catecholamine Release in Chromaffin Cells

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ABSTRACT

Neuronal and neuroendocrine L-type calcium channels (Cav1.2, Cav1.3) open readily at relatively low membrane potentials and allow Ca2+ to enter the cells near resting potentials. In this way, Cav1.2 and Cav1.3 shape the action potential waveform, contribute to gene expression, synaptic plasticity, neuronal differentiation, hormone secretion and pacemaker activity. In the chromaffin cells (CCs) of the adrenal medulla, Cav1.3 is highly expressed and is shown to support most of the pacemaking current that sustains action potential (AP) firings and part of the catecholamine secretion. Cav1.3 forms Ca2+-nanodomains with the fast inactivating BK channels and drives the resting SK currents. These latter set the inter-spike interval duration between consecutive spikes during spontaneous firing and the rate of spike adaptation during sustained depolarizations. Cav1.3 plays also a primary role in the switch from “tonic” to “burst” firing that occurs in mouse CCs when either the availability of voltage-gated Na channels (Nav) is reduced or the β2 subunit featuring the fast inactivating BK channels is deleted. Here, we discuss the functional role of these “neuron-like” firing modes in CCs and how Cav1.3 contributes to them. The open issue is to understand how these novel firing patterns are adapted to regulate the quantity of circulating catecholamines during resting condition or in response to acute and chronic stress.

No MeSH data available.


TTX leads to a dose-dependent switch into burst firing of MCCs. Top, representative current-clamp trace showing the action of increasing TTX concentration. Middle and bottom. better view of the effects of increasing TTX concentrations on AP waveforms and firing patterns at slower and faster (grey windows) time scales. Periods of activity were taken from the top panel (adapted from ref. [24]).
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Figure 4: TTX leads to a dose-dependent switch into burst firing of MCCs. Top, representative current-clamp trace showing the action of increasing TTX concentration. Middle and bottom. better view of the effects of increasing TTX concentrations on AP waveforms and firing patterns at slower and faster (grey windows) time scales. Periods of activity were taken from the top panel (adapted from ref. [24]).

Mentions: As in many brain regions, BK channels are highly expressed in RCCs [10, 86], MCCs [9, 19, 22] and bovine CCs (BCCs) [85, 87], To activate during physiological depolarization, BK channels need an intracellular Ca2+ concentration of at least 10 µM [84]. Such high concentrations occur only within “Ca2+-nanodomains” in the close vicinity of the Ca2+ source [88]. For this purpose, the neuronal BK channels are often co-localized to either the P/Q- [89], N- [90] or L-type [91] channels. RCCs and MCCs express two different BK channels that are predominantly coupled to L-type Cav1 channels [9, 79] and can be distinguished according to their inactivation kinetics: a fast-inactivating (BKi) and a slowly inactivating channel type (BKs) [9, 19, 78]. The BKi channel is typically expressed in CCs and gives rise to slowly adapting cell firing. The BKs channel has gating properties similar to the central neurons and smooth muscle BK channels and causes fast adapting cell firings [78]. Due to their strong voltage-dependence, BK channels contribute to the repolarization phase of the AP (AHP) [84, 86], influence the refractory period and regulate the firing rate of CCs. In MCCs, block of BK channels by paxilline significantly augments the firing frequency by delaying AP repolarization and slightly reducing the early phase of the AHP [19]. Notice that due to the tight Cav1-BK coupling also nifedipine, like paxilline, delays AP repolarization and reduces the early phase of the AHP in MCCs [9, 19] and RCCs [10, 78] (see Fig. 4 in ref [9]). However, due to the block of Cav1.3, the DHP either blocks or slows down the firing rate.


Ca v 1.3 Channels as Key Regulators of Neuron-Like Firings and Catecholamine Release in Chromaffin Cells
TTX leads to a dose-dependent switch into burst firing of MCCs. Top, representative current-clamp trace showing the action of increasing TTX concentration. Middle and bottom. better view of the effects of increasing TTX concentrations on AP waveforms and firing patterns at slower and faster (grey windows) time scales. Periods of activity were taken from the top panel (adapted from ref. [24]).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5384372&req=5

Figure 4: TTX leads to a dose-dependent switch into burst firing of MCCs. Top, representative current-clamp trace showing the action of increasing TTX concentration. Middle and bottom. better view of the effects of increasing TTX concentrations on AP waveforms and firing patterns at slower and faster (grey windows) time scales. Periods of activity were taken from the top panel (adapted from ref. [24]).
Mentions: As in many brain regions, BK channels are highly expressed in RCCs [10, 86], MCCs [9, 19, 22] and bovine CCs (BCCs) [85, 87], To activate during physiological depolarization, BK channels need an intracellular Ca2+ concentration of at least 10 µM [84]. Such high concentrations occur only within “Ca2+-nanodomains” in the close vicinity of the Ca2+ source [88]. For this purpose, the neuronal BK channels are often co-localized to either the P/Q- [89], N- [90] or L-type [91] channels. RCCs and MCCs express two different BK channels that are predominantly coupled to L-type Cav1 channels [9, 79] and can be distinguished according to their inactivation kinetics: a fast-inactivating (BKi) and a slowly inactivating channel type (BKs) [9, 19, 78]. The BKi channel is typically expressed in CCs and gives rise to slowly adapting cell firing. The BKs channel has gating properties similar to the central neurons and smooth muscle BK channels and causes fast adapting cell firings [78]. Due to their strong voltage-dependence, BK channels contribute to the repolarization phase of the AP (AHP) [84, 86], influence the refractory period and regulate the firing rate of CCs. In MCCs, block of BK channels by paxilline significantly augments the firing frequency by delaying AP repolarization and slightly reducing the early phase of the AHP [19]. Notice that due to the tight Cav1-BK coupling also nifedipine, like paxilline, delays AP repolarization and reduces the early phase of the AHP in MCCs [9, 19] and RCCs [10, 78] (see Fig. 4 in ref [9]). However, due to the block of Cav1.3, the DHP either blocks or slows down the firing rate.

View Article: PubMed Central - PubMed

ABSTRACT

Neuronal and neuroendocrine L-type calcium channels (Cav1.2, Cav1.3) open readily at relatively low membrane potentials and allow Ca2+ to enter the cells near resting potentials. In this way, Cav1.2 and Cav1.3 shape the action potential waveform, contribute to gene expression, synaptic plasticity, neuronal differentiation, hormone secretion and pacemaker activity. In the chromaffin cells (CCs) of the adrenal medulla, Cav1.3 is highly expressed and is shown to support most of the pacemaking current that sustains action potential (AP) firings and part of the catecholamine secretion. Cav1.3 forms Ca2+-nanodomains with the fast inactivating BK channels and drives the resting SK currents. These latter set the inter-spike interval duration between consecutive spikes during spontaneous firing and the rate of spike adaptation during sustained depolarizations. Cav1.3 plays also a primary role in the switch from “tonic” to “burst” firing that occurs in mouse CCs when either the availability of voltage-gated Na channels (Nav) is reduced or the β2 subunit featuring the fast inactivating BK channels is deleted. Here, we discuss the functional role of these “neuron-like” firing modes in CCs and how Cav1.3 contributes to them. The open issue is to understand how these novel firing patterns are adapted to regulate the quantity of circulating catecholamines during resting condition or in response to acute and chronic stress.

No MeSH data available.