GABAA receptor: a unique modulator of excitability, Ca2+ signaling, and catecholamine release of rat chromaffin cells

Abstract

The role of gamma-aminobutyric acid (GABA) in adrenal medulla chromaffin cell (CC) function is just beginning to unfold. GABA is stored in catecholamine (CA)-containing dense core granules and is presumably released together with CA, ATP, and opioids in response to physiological stimuli, playing an autocrine-paracrine role on CCs. The reported paradoxical "dual action" of GABA-R activation (enhancement of CA secretion and inhibition of synaptically evoked CA release) is only one aspect of GABA's multifaceted actions. In this review, we discuss recent physiological experiments on rat CCs in situ which suggest that GABA regulation of CC function may depend on the physiological context: During non-stressful conditions, GABA-R activation by endogenous GABA tonically inhibits acetylcholine release from splanchnic nerve terminals and decreases spontaneous Ca fluctuations in CCs, preventing unwanted CA secretion. During intense stress, splanchnic nerve terminals release acetylcholine, which depolarizes CCs and allows the Ca influx that triggers the release of CA and GABA. With time, CA secretion declines, due to voltage-independent inhibition of Cachannels and desensitization of cholinergic nicotinic receptors. Nonetheless, acute activation of GABA-R is depolarizing in about 50% of CCs, and thus GABA, acting as an autocrine/paracrine mediator, could help to maintain CA exocytosis under stress. GABA-R activation is not excitatory in about half of CCs' population because it hyperpolarizes them or elicits no response. This percentage possibly varies, depending on functional demands, since GABA-R-mediated actions are determined by the intracellular chloride concentration ([Cl] ) and therefore on the activity of cation-chloride co transporters, which is functionally regulated. These findings underscore a potential importance of a novel and complex GABA-mediated regulation of CC function and of CA secretion.

Cholinergic and peptidergic neurotransmission in the adrenal medulla: A dynamic control of stimulus‐secretion coupling

“…An intriguing finding is the facilitating effect of the GABA A receptor antagonist bicuculline on the release of catecholamine elicited by nicotinic receptor activation, indicating that (a) catecholamine secretion mediated by activation of nAChRs is under tonic inhibitory control of GABA and (b) GABA signaling may modulate rat chromaffin cell responsiveness to cholinergic synaptic inputs. In the same line, the blockade of presynaptic GABA A receptors by bicuculline enhances spontaneous synaptic current amplitude and frequency, a result that is indicative of the relief of spontaneous cholinergic neurotransmission …”

Oxytocin and Vasopressin, and the GABA Developmental Shift During Labor and Birth: Friends or Foes?

“…GABA exerts different effects notably on transmitter release in chromaffin cells. GABA exerts opposite effects in moderate and severe stress on catecholamine or acetylcholine release (Kataoka et al, 1984 ; Alejandre-García et al, 2018 ), a situation that is reminiscent of immature neurons (Harada et al, 2016 ). Similarly, GABA exerts diurnal day/night shifts of actions in the suprachiasmatic nucleus (Wagner et al, 1997 ; Irwin and Allen, 2009 ).…”