Minireview: aldosterone biosynthesis: electrically gated for our protection

Abstract

Aldosterone produced by adrenal zona glomerulosa (ZG) cells plays an important role in maintaining salt/water balance and, hence, blood pressure homeostasis. However, when dysregulated, aldosterone advances renal and cardiovascular disease states. Multiple steps in the steroidogenic pathway require Ca(2+), and the sustained production of aldosterone depends on maintained Ca(2+) entry into the ZG cell. Nevertheless, the recorded membrane potential of isolated ZG cells is extremely hyperpolarized, allowing the opening of only a small fraction of low-voltage-activated Ca(2+) channels of the Ca(v)3.x family, the major Ca(2+) conductance on the ZG cell membrane. As a consequence, to activate sufficient Ca(2+) channels to sustain the production of aldosterone, aldosterone secretagogs would be required to affect large decreases in membrane voltage, a requirement that is inconsistent with the exquisite sensitivity of aldosterone production in vivo to small changes (0.1 mm) in extracellular K(+). In this review, we evaluate the contribution of membrane voltage and voltage-dependent Ca(2+) channels to the control of aldosterone production and consider data highlighting the electrical excitability of the ZG cell. This intrinsic capacity of ZG cells to behave as electrical oscillators provides a platform from which to generate a recurring Ca(2+) signal that is compatible with the lengthy time course of steroidogenesis and provides an alternative model for the physiological regulation of aldosterone production that permits both amplitude and temporal modulation of the Ca(2+) signal.

Fig. 1.

Schematic model of electrically excitable ZG cell. Ang II increases the frequency of membrane potential oscillations in ZG cells, resulting in enhanced Ca²⁺ entry that acts at multiple sites to promote the production if aldosterone. The ZG electrical response to Ang II stimulation is mediated by the coordinated activities of multiple channel conductances. Transient inhibition of K⁺ channels via AT₁R activation produces a membrane depolarization and the opening of voltage-dependent Ca²⁺ channels. The activities of high-voltage dependent and/or Ca²⁺-activated K⁺ conductances participate in the restoration of baseline Vm, returning Ca²⁺ channels to a closed state from which they can open during the next oscillatory cycle. Green arrows indicate aldosterone promoting action, whereas red lines indicate basal inhibitory activities.