A role for T-type Ca²⁺channels in the synergistic control of aldosterone production by ANG II and K⁺

Abstract

Independently, plasma K+and ANG II stimulate aldosterone secretion from adrenal glomerulosa (AG) cells, but together they synergistically control production. We studied mechanisms to mediate this synergy using bovine AG cells studied under physiological conditions (in 1.25 mM Ca2+ at 37°C). Increasing K+ from 2 to 5 mM caused a potentiation of ANG II-induced aldosterone secretion and a substantial membrane depolarization (∼21 mV). ANG II inhibited a K+-selective conductance in both 2 and 5 mM K+ but caused only a slight depolarization because, under both conditions, membrane potential was close to the reversal potential of the ANG II-induced current. ANG II activated calcium/calmodulin-dependent protein kinase II (CaMKII) equivalently in 2 and 5 mM K+. However, CaMKII activation caused a hyperpolarizing shift in the activation of T-type Ca2+ channels, such that substantially more current was elicited at membrane potentials established by 5 mM K+. We propose that synergy in aldosterone secretion results from K+-induced depolarization and ANG II-induced modulation of T-type channel activation, such that together they promote enhanced steady-state Ca2+ flux.

TASK channel deletion in mice causes primary hyperaldosteronism

“…Across species, low-voltage-activated Cav3.2 channels of the Cav3.0 family are the major calcium conductance of the ZG cell, and although mostly closed at rest, they are available for opening during cell depolarization (18). However, ZG cells do not support Na-dependent action potentials and maintain a very negative resting membrane voltage (14,16,19), at which the open probability of even Cav3.2 channels is very low (35). Our experiments show that TASK channels are a dominant K conductance of the ZG cell that serves to clamp the membrane to these hyperpolarized voltages, effectively restraining the production of aldosterone.…”

“…Ang II and extracellular K are potent independent regulators of aldosterone production, yet the strength of these agonists in the physiological setting depends on their combined activities and their synergy (11)(12)(13)(14). Small elevations in plasma potassium within the physiological range increase the sensitivity of ZG cells to stimulation by Ang II (13,15).…”

“…Small elevations in plasma potassium within the physiological range increase the sensitivity of ZG cells to stimulation by Ang II (13,15). In this setting, both K and Ang II mediate membrane depolarization of ZG cells (14,16) to enhance the opening of Ang II-modulated, low-voltage-activated, Ca channels (Cav3.2) whose activity underlies the in vivo control of aldosterone production (17,18).…”

“…Adrenal ZG cells maintain a hyperpolarized resting membrane voltage that is negative to Ϫ70 mV (14,16,19). Although macroscopic K currents recorded from rat, bovine, and human ZG cells have revealed the expression of multiple voltagedependent K conductances, the mRNA for TWIK-related acidsensitive K (TASK)-1 and TASK-3 subunits is particularly abundant (20)(21)(22)(23).…”

“…TASK-1 and TASK-3 channels are inhibited by extracellular protons in the physiological range and by hormones that activate G q -coupled receptors (26). Direct inhibition of TASK-1 or TASK-3 channels by activation of the AT 1A or AT 1B receptor or deletion of these channels from ZG cells would be expected to depolarize ZG cell membrane potential and produce an increase in voltage-dependent Ca channel activity that drives the production of aldosterone (14).…”