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GABA Signaling and Neuroactive Steroids in Adrenal Medullary Chromaffin Cells.

Harada K, Matsuoka H, Fujihara H, Ueta Y, Yanagawa Y, Inoue M - Front Cell Neurosci (2016)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell and Systems Physiology, University of Occupational and Environmental Health School of Medicine Kitakyushu, Japan.

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.

No MeSH data available.


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Enhancement of GABAA receptor channel activity by allopregnanolone. (A) Whole-cell currents recorded from a dissociated guinea-pig chromaffin cell at −60 mV. The traces were obtained from the same cell. GABA at 3 or 10 μM was bath applied during the indicated period (bars) in the absence and presence of 0.01 or 0.1 μM allopregnanolone (interrupted lines). (B) Dose-response curves for GABA-induced currents at the plateau level in the absence (•) and presence (▴) of 0.1 μM allopregnanolone. The lines show fits of logistic equations with IMaxs of 1.38 and 1.31, slope factors of 2.88 and 2.83, and EC50s of 7.2 and 0.3 μM in the absence and presence of allopregnanolone, respectively. Plateau amplitudes of GABA-induced currents are expressed as fractions of those of 10 μM GABA currents in the same cells. The data represent mean ± SEM. (A,B) Are reproduced from Inoue et al. (2013).
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Figure 5: Enhancement of GABAA receptor channel activity by allopregnanolone. (A) Whole-cell currents recorded from a dissociated guinea-pig chromaffin cell at −60 mV. The traces were obtained from the same cell. GABA at 3 or 10 μM was bath applied during the indicated period (bars) in the absence and presence of 0.01 or 0.1 μM allopregnanolone (interrupted lines). (B) Dose-response curves for GABA-induced currents at the plateau level in the absence (•) and presence (▴) of 0.1 μM allopregnanolone. The lines show fits of logistic equations with IMaxs of 1.38 and 1.31, slope factors of 2.88 and 2.83, and EC50s of 7.2 and 0.3 μM in the absence and presence of allopregnanolone, respectively. Plateau amplitudes of GABA-induced currents are expressed as fractions of those of 10 μM GABA currents in the same cells. The data represent mean ± SEM. (A,B) Are reproduced from Inoue et al. (2013).

Mentions: Exposure of guinea-pig adrenal chromaffin cells to allopregnanolone resulted in an enhancement of GABAA receptor channel activity (Inoue et al., 2013). In the presence of 0.01 and 0.1 μM allopregnanolone, the amplitude of currents induced by 3 μM GABA increased by 1.1 and 20-fold (Figure 5A). In addition, the dose-response curve for steady-state GABA-induced currents was shifted toward the left and the EC50 decreased by 24-fold in 0.1 μM allopregnanolone (from 7.2 μM to 0.3 μM; Figure 5B). This result indicates that 0.1 μM GABA, which does not induce any channel activity in the absence of allopregnanolone, is able to produce a sustained current in the presence of 0.1 μM allopregnanolone. The blood concentration of GABA in humans is about 0.1 μM (Petty, 1994), but the concentration of GABA in the extracellular space of the adrenal medulla is not known. Since GABA is thought to be released from chromaffin cells (Kataoka et al., 1984), the concentration of GABA in the vicinity of chromaffin cells is expected to be larger than the 0.1 μM concentration observed in the blood. The plasma concentration of allopregnanolone in rats has been reported to be a few nanomolar levels at rest and to be elevated to 20 nM in stress, such as swimming (Purdy et al., 1991). However, the adrenal vein drains the venous blood from the adrenal cortex through the medulla and so it is very likely that the concentration of allopregnanolone (synthesized in the cortex) will be elevated over that in the general circulation. In light of the concentrations at which the GABAA receptor channel activity in chromaffin cells is enhanced, allopregnanolone may play an important role in modulating the para/autocrine function of GABA in adrenal medullae.


GABA Signaling and Neuroactive Steroids in Adrenal Medullary Chromaffin Cells.

Harada K, Matsuoka H, Fujihara H, Ueta Y, Yanagawa Y, Inoue M - Front Cell Neurosci (2016)

Enhancement of GABAA receptor channel activity by allopregnanolone. (A) Whole-cell currents recorded from a dissociated guinea-pig chromaffin cell at −60 mV. The traces were obtained from the same cell. GABA at 3 or 10 μM was bath applied during the indicated period (bars) in the absence and presence of 0.01 or 0.1 μM allopregnanolone (interrupted lines). (B) Dose-response curves for GABA-induced currents at the plateau level in the absence (•) and presence (▴) of 0.1 μM allopregnanolone. The lines show fits of logistic equations with IMaxs of 1.38 and 1.31, slope factors of 2.88 and 2.83, and EC50s of 7.2 and 0.3 μM in the absence and presence of allopregnanolone, respectively. Plateau amplitudes of GABA-induced currents are expressed as fractions of those of 10 μM GABA currents in the same cells. The data represent mean ± SEM. (A,B) Are reproduced from Inoue et al. (2013).
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Figure 5: Enhancement of GABAA receptor channel activity by allopregnanolone. (A) Whole-cell currents recorded from a dissociated guinea-pig chromaffin cell at −60 mV. The traces were obtained from the same cell. GABA at 3 or 10 μM was bath applied during the indicated period (bars) in the absence and presence of 0.01 or 0.1 μM allopregnanolone (interrupted lines). (B) Dose-response curves for GABA-induced currents at the plateau level in the absence (•) and presence (▴) of 0.1 μM allopregnanolone. The lines show fits of logistic equations with IMaxs of 1.38 and 1.31, slope factors of 2.88 and 2.83, and EC50s of 7.2 and 0.3 μM in the absence and presence of allopregnanolone, respectively. Plateau amplitudes of GABA-induced currents are expressed as fractions of those of 10 μM GABA currents in the same cells. The data represent mean ± SEM. (A,B) Are reproduced from Inoue et al. (2013).
Mentions: Exposure of guinea-pig adrenal chromaffin cells to allopregnanolone resulted in an enhancement of GABAA receptor channel activity (Inoue et al., 2013). In the presence of 0.01 and 0.1 μM allopregnanolone, the amplitude of currents induced by 3 μM GABA increased by 1.1 and 20-fold (Figure 5A). In addition, the dose-response curve for steady-state GABA-induced currents was shifted toward the left and the EC50 decreased by 24-fold in 0.1 μM allopregnanolone (from 7.2 μM to 0.3 μM; Figure 5B). This result indicates that 0.1 μM GABA, which does not induce any channel activity in the absence of allopregnanolone, is able to produce a sustained current in the presence of 0.1 μM allopregnanolone. The blood concentration of GABA in humans is about 0.1 μM (Petty, 1994), but the concentration of GABA in the extracellular space of the adrenal medulla is not known. Since GABA is thought to be released from chromaffin cells (Kataoka et al., 1984), the concentration of GABA in the vicinity of chromaffin cells is expected to be larger than the 0.1 μM concentration observed in the blood. The plasma concentration of allopregnanolone in rats has been reported to be a few nanomolar levels at rest and to be elevated to 20 nM in stress, such as swimming (Purdy et al., 1991). However, the adrenal vein drains the venous blood from the adrenal cortex through the medulla and so it is very likely that the concentration of allopregnanolone (synthesized in the cortex) will be elevated over that in the general circulation. In light of the concentrations at which the GABAA receptor channel activity in chromaffin cells is enhanced, allopregnanolone may play an important role in modulating the para/autocrine function of GABA in adrenal medullae.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell and Systems Physiology, University of Occupational and Environmental Health School of Medicine Kitakyushu, Japan.

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.

No MeSH data available.


Related in: MedlinePlus