GABA Signaling and Neuroactive Steroids in Adrenal Medullary Chromaffin Cells

Abstract

Gamma-aminobutyric acid (GABA) is produced not only in the brain, but also in endocrine cells by the two isoforms of glutamic acid decarboxylase (GAD), GAD65 and GAD67. In rat adrenal medullary chromaffin cells only GAD67 is expressed, and GABA is stored in large dense core vesicles (LDCVs), but not synaptic-like microvesicles (SLMVs). The α3β2/3γ2 complex represents the majority of GABAA receptors expressed in rat and guinea pig chromaffin cells, whereas PC12 cells, an immortalized rat chromaffin cell line, express the α1 subunit as well as the α3. The expression of α3, but not α1, in PC12 cells is enhanced by glucocorticoid activity, which may be mediated by both the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR). GABA has two actions mediated by GABAA receptors in chromaffin cells: it induces catecholamine secretion by itself and produces an inhibition of synaptically evoked secretion by a shunt effect. Allopregnanolone, a neuroactive steroid which is secreted from the adrenal cortex, produces a marked facilitation of GABAA receptor channel activity. Since there are no GABAergic nerve fibers in the adrenal medulla, GABA may function as a para/autocrine factor in the chromaffin cells. This function of GABA may be facilitated by expression of the immature isoforms of GAD and GABAA receptors and the lack of expression of plasma membrane GABA transporters (GATs). In this review, we will consider how the para/autocrine function of GABA is achieved, focusing on the structural and molecular mechanisms for GABA signaling.

Molecular determinants of the adrenal gland functioning related to stress-sensitive hypertension in ISIAH rats

“…However, gamma-aminobutyric acid (GABA) is produced not only in the brain, but also in endocrine cells including rat adrenal medullary chromaffin cells. Since there are no GABAergic nerve fibers in the adrenal medulla, GABA may function as a para/autocrine factor [44]. The functional role of the elevated transcription of Gabbr1 in adrenal glands is not known and has to be studied, as it might be essential for stress-sensitive hypertension development in ISIAH rats.…”

Effect of developmental NMDAR antagonism with CGP 39551 on aspartame-induced hypothalamic and adrenal gene expression

“…Fig 5A shows a network created in IPA involving glutamatergic and GABAergic DEGs which were both highly upregulated in response to aspartame exposure. In adrenal chromaffin cells, GABA functions as a paracrine and autocrine modulator of catecholamine synthesis via GABA A receptors [ 68 ]; and ASP treatment upregulated the expression of Gabra1 , Gabra3 , Gabrb2 , Gabrg2 and Gabra5 by 47, 1.9, 13.5, 6 and 12-fold respectively (P≤0.05). GABA exhibits dual actions in adrenal cells, enhancing catecholamine secretion at low levels whilst attenuating the release of catecholamines elicited by hyperstimulation of nerve impulses.…”

“…In the brain, GABA is the main inhibitory neurotransmitter however in endocrine tissues such as the adrenal and pancreatic glands GABA may function as a para/autocrine factor [ 100 ]. In adrenal chromaffin cells, GABA receptors are mainly composed of pentamers made up of α3β2/3γ2 subunits [ 68 ], and the expression of all 3 transcripts were upregulated in ASP-exposed mice. Neuronal GABA is synthesized from glutamic acid by glutamate decarboxylase (GAD), an enzyme which is encoded by the product of two different genes: GAD65 and GAD67 both of which were also upregulated in the adrenals of ASP-exposed mice, as were GABA transporters Slc6a1 and Slc6a11 .…”

“…Neuronal GABA is synthesized from glutamic acid by glutamate decarboxylase (GAD), an enzyme which is encoded by the product of two different genes: GAD65 and GAD67 both of which were also upregulated in the adrenals of ASP-exposed mice, as were GABA transporters Slc6a1 and Slc6a11 . Recent studies have shown that GABA might have a dual function in adrenal cells: inducing catecholamine secretion potentially leading to increased blood glucose levels [ 68 , 101 ], and because it reduces the membrane depolarization resulting from electrical nerve stimulation, GABA can attenuate the large release of catecholamine which would be elicited by a barrage of nerve impulses [ 68 ].…”

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 ).…”