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

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.


Reducing NaV availability by TTX inverts net current during the AHP from outward to inward. a) Top, AP-clamp experiment showing representative control spike. Middle, Kv currents (ligh grey traces) were measured in a Tyrode standard solution with TTX (300 nM) and Cd2+ (200 μM). Ca2+ currents (black) were measured in the presence of TTX (300 nM) and high extracellular TEA (135 mM). Ca2+-activated K+ currents (dark grey) were obtained by subtracting from a control recording in Tyrode standard with 300 nM TTX the KV and the Ca2+ current. Bottom, close up of the middle panel. The dashed rectangles indicate the AHP phase and the respective currents that sustain it. b) same as for a, using a spike doublet fired after complete block of Nav currents with 300 nM TTX. Bottom-left inset in a: net current amplitudes measured during the AHP phase indicated by the dashed rectangles. Bottom-left inset in b: Ca2+ charge entering the cell during the AHP phase calculated by integrating the corresponding Ca2+ inward current (ICa) shown in full to the right (adapted from ref. [24]).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC5384372&req=5

Figure 5: Reducing NaV availability by TTX inverts net current during the AHP from outward to inward. a) Top, AP-clamp experiment showing representative control spike. Middle, Kv currents (ligh grey traces) were measured in a Tyrode standard solution with TTX (300 nM) and Cd2+ (200 μM). Ca2+ currents (black) were measured in the presence of TTX (300 nM) and high extracellular TEA (135 mM). Ca2+-activated K+ currents (dark grey) were obtained by subtracting from a control recording in Tyrode standard with 300 nM TTX the KV and the Ca2+ current. Bottom, close up of the middle panel. The dashed rectangles indicate the AHP phase and the respective currents that sustain it. b) same as for a, using a spike doublet fired after complete block of Nav currents with 300 nM TTX. Bottom-left inset in a: net current amplitudes measured during the AHP phase indicated by the dashed rectangles. Bottom-left inset in b: Ca2+ charge entering the cell during the AHP phase calculated by integrating the corresponding Ca2+ inward current (ICa) shown in full to the right (adapted from ref. [24]).

Mentions: During burst firing, brief periods of high frequency firing are separated by relatively long gaps of no activity. Spikes fire in bursts on top of a slow-wave depolarization plateau that lasts for the whole burst duration. AP-clamp experiments show clearly that while the net current during the AHP of single control spikes is outward, the current during the intraburst interval is net inward and carried by Ca2+ (dashed rectangles in Fig. 5a). Broadening of APs during cell depolarization and bursts of APs in the presence of TTX causes a ten-fold prolongation of Ca2+ currents (bottom inset in Fig. 5b) that, despite the lower amplitudes, carries about four-fold more Ca2+ charges inside the cell [24], demostrating that Ca2+ currents are the main source of the slow depolarization plateau. In conclusion, the incoming Ca2+, together with a lack of sufficient outward K+ current is the triggering event of burst firing when Nav channels availability is strongly attenuated.


Ca v 1.3 Channels as Key Regulators of Neuron-Like Firings and Catecholamine Release in Chromaffin Cells
Reducing NaV availability by TTX inverts net current during the AHP from outward to inward. a) Top, AP-clamp experiment showing representative control spike. Middle, Kv currents (ligh grey traces) were measured in a Tyrode standard solution with TTX (300 nM) and Cd2+ (200 μM). Ca2+ currents (black) were measured in the presence of TTX (300 nM) and high extracellular TEA (135 mM). Ca2+-activated K+ currents (dark grey) were obtained by subtracting from a control recording in Tyrode standard with 300 nM TTX the KV and the Ca2+ current. Bottom, close up of the middle panel. The dashed rectangles indicate the AHP phase and the respective currents that sustain it. b) same as for a, using a spike doublet fired after complete block of Nav currents with 300 nM TTX. Bottom-left inset in a: net current amplitudes measured during the AHP phase indicated by the dashed rectangles. Bottom-left inset in b: Ca2+ charge entering the cell during the AHP phase calculated by integrating the corresponding Ca2+ inward current (ICa) shown in full to the right (adapted from ref. [24]).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 5: Reducing NaV availability by TTX inverts net current during the AHP from outward to inward. a) Top, AP-clamp experiment showing representative control spike. Middle, Kv currents (ligh grey traces) were measured in a Tyrode standard solution with TTX (300 nM) and Cd2+ (200 μM). Ca2+ currents (black) were measured in the presence of TTX (300 nM) and high extracellular TEA (135 mM). Ca2+-activated K+ currents (dark grey) were obtained by subtracting from a control recording in Tyrode standard with 300 nM TTX the KV and the Ca2+ current. Bottom, close up of the middle panel. The dashed rectangles indicate the AHP phase and the respective currents that sustain it. b) same as for a, using a spike doublet fired after complete block of Nav currents with 300 nM TTX. Bottom-left inset in a: net current amplitudes measured during the AHP phase indicated by the dashed rectangles. Bottom-left inset in b: Ca2+ charge entering the cell during the AHP phase calculated by integrating the corresponding Ca2+ inward current (ICa) shown in full to the right (adapted from ref. [24]).
Mentions: During burst firing, brief periods of high frequency firing are separated by relatively long gaps of no activity. Spikes fire in bursts on top of a slow-wave depolarization plateau that lasts for the whole burst duration. AP-clamp experiments show clearly that while the net current during the AHP of single control spikes is outward, the current during the intraburst interval is net inward and carried by Ca2+ (dashed rectangles in Fig. 5a). Broadening of APs during cell depolarization and bursts of APs in the presence of TTX causes a ten-fold prolongation of Ca2+ currents (bottom inset in Fig. 5b) that, despite the lower amplitudes, carries about four-fold more Ca2+ charges inside the cell [24], demostrating that Ca2+ currents are the main source of the slow depolarization plateau. In conclusion, the incoming Ca2+, together with a lack of sufficient outward K+ current is the triggering event of burst firing when Nav channels availability is strongly attenuated.

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.