The Permeation of Divalent Cations Through CNGA1 and CNGB1 Channels

Abstract

Pituitary adenylate cyclase activating polypeptide (PACAP) is a peptide transmitter released from the sympathetic splanchnic nerve to stimulate neurosecretory chromaffin cells of the adrenal medulla. Previous studies have shown that PACAP is preferentially released under heightened splanchnic firing of the sympathetic stress response. PACAP-dependent stimulation results in an immediate and robust Ca 2þ -dependent catecholamine secretion from chromaffin cells. Yet, PACAP stimulation does not evoke action potential firing in the chromaffin cell. Rather PACAP treatment elicits a sub-threshold membrane depolarization to approximately À50 mV. However, chromaffin cells voltage-clamped at the ''PACAP potential'' (À55mV) do not exhibit the same robust secretion as PACAP-treated cells, suggesting that PACAP may effect voltage-gated calcium entry through more than a simple sub-threshold depolarization. We used perforated patch electrophysiological recordings conducted in adrenal tissue slices to investigate the mechanism by which PACAP evokes rapid and robust Ca 2þ influx and catecholamine secretion. We provide evidence that PACAP excitation includes a facilitation of Ca 2þ influx through low-voltage activated (LVA) Ca 2þ channels. Pharmacological isolation and molecular classification indicate that the target channel is likely CaV3.2. Thus, PACAPevoked adrenal secretion is likely through a parallel membrane depolarization and functional facilitation of LVA calcium channels.