Role of voltage-gated calcium channels in the regulation of aldosterone production from zona glomerulosa cells of the adrenal cortex

Abstract

Zona glomerulosa cells (ZG) of the adrenal gland constantly integrate fluctuating ionic, hormonal and paracrine signals to control the synthesis and secretion of aldosterone. These signals modulate Ca²⁺ levels, which provide the critical second messenger to drive steroid hormone production. Angiotensin II is a hormone known to modulate the activity of voltage-dependent L- and T-type Ca²⁺ channels that are expressed on the plasma membrane of ZG cells in many species. Because the ZG cell maintains a resting membrane voltage of approximately -85 mV and has been considered electrically silent, low voltage-activated T-type Ca²⁺ channels are assumed to provide the primary Ca²⁺ signal that drives aldosterone production. However, this view has recently been challenged by human genetic studies identifying somatic gain-of-function mutations in L-type Ca_V 1.3 channels in aldosterone-producing adenomas of patients with primary hyperaldosteronism. We provide a review of these assumptions and challenges, and update our understanding of the state of the ZG cell in a layer in which native cellular associations are preserved. This updated view of Ca²⁺ signalling in ZG cells provides a unifying mechanism that explains how transiently activating Ca_V 3.2 channels can generate a significant and recurring Ca²⁺ signal, and how Ca_V 1.3 channels may contribute to the Ca²⁺ signal that drives aldosterone production.

Figure 1. A working model of the ZG pacemaker

At the start of the oscillatory cycle (V _m = −85 mV), depolarizing conductance(s) (X_v) elicit the opening of low voltage‐activated Ca_v3.2 channels which further depolarize V _m and enable the opening of high voltage‐activated Ca_v1.3 channels. Ca²⁺ influx and a reduced V _m recruits the activity of Ca²⁺‐dependent K⁺ channels that return V _m to −85 mV to begin another oscillatory cycle.