Anterior pituitary cells excited by GABA


The pituitary, sometimes called the master gland due to its governance over other glands, consists of three distinct anatomical and functional parts: posterior, intermediate (pars intermedia) and anterior lobes (Fig. 1). While the posterior pituitary consists of axon terminals originating from neurons with somata in the hypothalamus, cells in the pars intermedia release peptidergic hormones under the control of neurotransmitters released into the synaptic cleft from the innervating neurons. On the other hand, the secretory activity of anterior pituitary cells, which control important bodily functions including growth, development, reproduction and responses to stress, release hormones in response to blood-borne hypothalamic factors. Following their interaction with specific surface membrane receptors and subsequent activation of intracellular signalling mechanisms they control exocytosis and thus the secretory output from anterior pituitary cells.

Figure 1.

Diagram depicting hypothalamus pituitary gland and an anterior pituitary cell with the GABAA receptor, Na+-K-2Cl co-transporter (NKCCi), the K+-Cl co-transporter (KCC2), voltage-dependent calcium channel (VDCC).

The paper by Zemkova et al. (2008) in this issue of The Journal of Physiology, brings a new insight into the regulation of anterior pituitary cells. It seems that a novel regulating factor, γ-aminobutyric acid (GABA), will have to be firmly positioned into the list of factors stimulating hormone release from these cells. Although it has been known previously that anterior pituitary cells express ionotropic and metabotropic GABA receptors which mediate the secretory hormonal output from these cells (Anderson & Mitchell, 1986; Nakayama et al. 2006), it was unclear how the ionotropic GABA receptors, which gate chloride-specific channels, function in the stimulus–secretion coupling. Specifically, it was controversial whether GABA was stimulatory or inhibitory for the secretory output of anterior pituitary cells.

To address these issues Zemkova et al. (2008) first used molecular biology techniques to study the expression of molecular subunits of GABAA receptor channels in cultured anterior pituitary cells from postpubertal female rats and immortalized αT3-1 and GH3 clonal pituitary cells. Interestingly, mRNAs for all GABAA receptor subunits were found to be expressed in pituitary cells and α11 subunit proteins are present in all secretory cells. Second, by using electrophysiology to voltage clamp gramicidin-perforated cells to monitor GABA-induced currents, they have shown that GABA-induced dose-dependent increases in current amplitude were inhibited by bicuculline and picrotoxin, inhibitors of GABAA receptor channels, and facilitated by diazepam and zolpidem in a concentration-dependent manner. Third, they used fluorescence methods to test whether the application of GABA and the GABAA receptor agonist muscimol affected cytosolic calcium activity, an important cytosolic stimulus of anterior pituitary cell secretory activity. Since both GABA and muscimol caused a rapid and transient increase in intracellular calcium, whereas the GABAB receptor agonist baclofen was ineffective, their data are consistent with the view that chloride-mediated depolarization activates voltage-gated calcium channels. Furthermore, the GABAA channel reversal potential for chloride ions was positive to the resting membrane potential in most cells and the activation of ion channels by GABA resulted in depolarization of cells. This prompted Zemkova et al. (2008) to consider the mechanism of chloride homeostasis, which in most brain cells is controlled by NKCC1 and KCC2, two electrically neutral cation/chloride cotransporters. The ubiquitously expressed NKCC1 derives energy from the electrochemical gradient for Na+ to take up Cl, promoting cytosolic accumulation of Cl, whereas KCC2 facilitates Cl extrusion coupled to the K+ gradient (Fiumelli & Woodin, 2007). The experiments have shown that the mRNA expression of NKCC1 greatly exceeded that of KCC2, which is consistent with the relatively positive reversal potential for chloride currents.

While the results of Zemkova et al. (2008) establish the excitatory role of GABA in anterior pituitary cells, a number of questions have now been opened. For example, we will have to consider that GABA is now listed as a regulatory factor of anterior pituitary cells. However, it is unclear if it is delivered from the hypothalamus via the portal vascular system. While GABA is the major inhibitory neurotransmitter in the central nervous system and is released from nerve terminals innervating pars intermedia cells (Schneggenburger & López-Barneo, 1992), the mode of delivery of GABA to the cells in the anterior pituitary is probably different. Is the source of GABA the portal vasculature capturing GABA released from neurons in the median eminence? It is known that radioactive GABA readily accumulates in the pituitary (Kuroda et al. 2000; Duvilanski et al. 2000). Is it possible that GABA is released from anterior pituitary cells and thus can be considered an autocrine regulator? These questions will have to be addressed in the future.