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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.


Related in: MedlinePlus

Biosynthetic pathway of adrenal steroids. The enzymes shown mediate the conversion of steroids in the indicated step(s). The names of steroids are abbreviated: THP, 3α, 5α-tetrahydroprogesterone or allopregnanolone; DHP, 5α-dihydroprogesterone; THDOC, 3α, 5α-tetrahydrodeoxycorticosterone; DHDOC, 5α-dehydrodeoxycorticosterone; DHC, dehydrocorticosterone; DOC, 11-deoxycorticosterone; 17-OH preg, 17-OH pregnenolone; 17-OH prog, 17-OH progesterone; DHEA, dehydroepiandrosterone; DHEAS, DHEA sulfate. 3αHSD, 3α-hydroxysteroid dehydrogenase. The steroids marked by single and double asterisks are positive and negative allosteric modulators of GABAA receptors, respectively.
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Figure 4: Biosynthetic pathway of adrenal steroids. The enzymes shown mediate the conversion of steroids in the indicated step(s). The names of steroids are abbreviated: THP, 3α, 5α-tetrahydroprogesterone or allopregnanolone; DHP, 5α-dihydroprogesterone; THDOC, 3α, 5α-tetrahydrodeoxycorticosterone; DHDOC, 5α-dehydrodeoxycorticosterone; DHC, dehydrocorticosterone; DOC, 11-deoxycorticosterone; 17-OH preg, 17-OH pregnenolone; 17-OH prog, 17-OH progesterone; DHEA, dehydroepiandrosterone; DHEAS, DHEA sulfate. 3αHSD, 3α-hydroxysteroid dehydrogenase. The steroids marked by single and double asterisks are positive and negative allosteric modulators of GABAA receptors, respectively.

Mentions: Neuroactive steroids, such as allopregnanolone, are produced in adrenal glands of mammals including rats (Corpéchot et al., 1993) and humans (Genazzani et al., 1998) and are known to act on GABAA receptors (Zhu and Vicini, 1997; Belelli and Lambert, 2005). Therefore, to elucidate the function of GABA signaling in the adrenal medulla, it will be important to take into account the effects of neuroactive steroids. Figure 4 illustrates the biosynthetic pathway for adrenal steroids, in which positive (Lambert et al., 1995; Reddy and Rogawski, 2002) and negative (Park-Chung et al., 1999) allosteric modulators are denoted by single and double asterisks, respectively. The adrenal cortex of rats and mice lacks the expression of P450c17 (Le Goascogne et al., 1991; Figure 4). Therefore, the main glucocorticoid in such rodents is corticosterone, whereas in other mammals including humans it is cortisol. The lack of P450c17 results in a loss in production of dehydroepiandrosterone (DHEA) and its sulfated form or DHEAS in the adrenal cortex. In rat gonads where P450c17 is expressed, DHEAS is produced. In contrast, allopregnanolone (THP in Figure 4) is produced in the adrenal glands of rats (Corpéchot et al., 1993) and humans (Genazzani et al., 1998). It is synthesized in two steps from progesterone. 5α-reductase, which was immunologically detected in the zona fasciculata of rat adrenal glands (Yokoi et al., 1998), catalyzes the conversion from progesterone to 3α-hydroprogesterone (DHP), which is further converted to allopregnanolone by 3α-hydrosterone dehydrogenase.


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)

Biosynthetic pathway of adrenal steroids. The enzymes shown mediate the conversion of steroids in the indicated step(s). The names of steroids are abbreviated: THP, 3α, 5α-tetrahydroprogesterone or allopregnanolone; DHP, 5α-dihydroprogesterone; THDOC, 3α, 5α-tetrahydrodeoxycorticosterone; DHDOC, 5α-dehydrodeoxycorticosterone; DHC, dehydrocorticosterone; DOC, 11-deoxycorticosterone; 17-OH preg, 17-OH pregnenolone; 17-OH prog, 17-OH progesterone; DHEA, dehydroepiandrosterone; DHEAS, DHEA sulfate. 3αHSD, 3α-hydroxysteroid dehydrogenase. The steroids marked by single and double asterisks are positive and negative allosteric modulators of GABAA receptors, respectively.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4834308&req=5

Figure 4: Biosynthetic pathway of adrenal steroids. The enzymes shown mediate the conversion of steroids in the indicated step(s). The names of steroids are abbreviated: THP, 3α, 5α-tetrahydroprogesterone or allopregnanolone; DHP, 5α-dihydroprogesterone; THDOC, 3α, 5α-tetrahydrodeoxycorticosterone; DHDOC, 5α-dehydrodeoxycorticosterone; DHC, dehydrocorticosterone; DOC, 11-deoxycorticosterone; 17-OH preg, 17-OH pregnenolone; 17-OH prog, 17-OH progesterone; DHEA, dehydroepiandrosterone; DHEAS, DHEA sulfate. 3αHSD, 3α-hydroxysteroid dehydrogenase. The steroids marked by single and double asterisks are positive and negative allosteric modulators of GABAA receptors, respectively.
Mentions: Neuroactive steroids, such as allopregnanolone, are produced in adrenal glands of mammals including rats (Corpéchot et al., 1993) and humans (Genazzani et al., 1998) and are known to act on GABAA receptors (Zhu and Vicini, 1997; Belelli and Lambert, 2005). Therefore, to elucidate the function of GABA signaling in the adrenal medulla, it will be important to take into account the effects of neuroactive steroids. Figure 4 illustrates the biosynthetic pathway for adrenal steroids, in which positive (Lambert et al., 1995; Reddy and Rogawski, 2002) and negative (Park-Chung et al., 1999) allosteric modulators are denoted by single and double asterisks, respectively. The adrenal cortex of rats and mice lacks the expression of P450c17 (Le Goascogne et al., 1991; Figure 4). Therefore, the main glucocorticoid in such rodents is corticosterone, whereas in other mammals including humans it is cortisol. The lack of P450c17 results in a loss in production of dehydroepiandrosterone (DHEA) and its sulfated form or DHEAS in the adrenal cortex. In rat gonads where P450c17 is expressed, DHEAS is produced. In contrast, allopregnanolone (THP in Figure 4) is produced in the adrenal glands of rats (Corpéchot et al., 1993) and humans (Genazzani et al., 1998). It is synthesized in two steps from progesterone. 5α-reductase, which was immunologically detected in the zona fasciculata of rat adrenal glands (Yokoi et al., 1998), catalyzes the conversion from progesterone to 3α-hydroprogesterone (DHP), which is further converted to allopregnanolone by 3α-hydrosterone dehydrogenase.

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