Endothelin Action on Pituitary Lactotrophs: One Receptor, Many GTP-Binding Proteins

Abstract

The secretion of prolactin (PRL) from pituitary lactotrophs of the rat is predominantly under inhibitory control exerted by dopamine (DA) of hypothalamic origin (1). Other PRL-inhibiting substances of hypothalamic origin include somatostatin and endothelin (ET) (2). The latter is the focus of a recent article from the Stojilkovic lab (3) and of this report. In addition to the PRL-inhibiting substances, a host of candidate PRL-releasing hormones, also of hypothalamic origin, exist (2). These include thyrotropin-releasing hormone (TRH), vasoactive intestinal polypeptide, angiotensin II, oxytocin (OT), and even DA itself (2). Each has well-described receptors on the lactotroph membrane and, in most cases, has well-defined postreceptor transduction cascades that regulate PRL secretion. These include the activation of excitatory or inhibitory guanosine triphosphate (GTP)-binding proteins (G proteins) (G s , G q , and G i/o ), which activate or inhibit adenylyl cyclase with downstream effects on adenosine 3′,5′-monophosphate (cAMP) formation or which activate phospholipase C (PLC). Although the nature of these pathways differs, they share one final common denominator: They each regulate PRL secretion by affecting the intracellular levels of calcium, the key ion evoking PRL exocytosis.The ETs are a family of vasoconstrictor peptides that were found in (4) and later purified from tissue culture media of vascular endothelial cells (5). Three different ET isopeptides encoded by three separate genes were identified and designated ET-1, -2, and -3 (6). Similarly, three types of ET receptors have been identified and cloned (7-9). In pituitary cells, endothelins operate through ET A receptors, which have greater affinity for ET-1 and ET-2 than for ET-3 (10). Early evidence suggested that the ETs may affect pituitary hormone secretion. Indeed, their mRNAs are found in the pituitary gland and in hypothalamic magnocellular nuclei (11,12). Moreover, ETs and their receptors are found in the anterior lobe of the pituitary gland (13), and ET-like immunoreactivity is found in lactotrophs, gonadotrophs, and somatotrophs (14). This suggests that the ETs may be autocrine regulators of pituitary hormone secretion (15).Other lines of evidence indicate that the ETs play a role in the secretion of hormones from the anterior pituitary gland. It has been reported that ETs acting at ET A receptors (10) diminish PRL secretion while enhancing luteinizing hormone, follicle-stimulating hormone, and thyroid-stimulating hormone secretion in vitro (16)(17)(18). In the presence of DA, the PRL secretory response to ET-1 is biphasic, consisting of an initial rapid high-amplitude stimulatory phase followed by a sustained modest elevation as long as ET-1 is present (19). In the absence of DA, the initial ET-mediated stimulatory response is followed by a sustained inhibition of PRL secretion, which lasts for tens of minutes after the removal of the ET-1 (19). The effect of ET-1 in lactotrophs is partially mediated by the activation of large-conductance Ca ...

Dopamine Inhibits Basal Prolactin Release in Pituitary Lactotrophs through Pertussis Toxin-Sensitive and -Insensitive Signaling Pathways

“…In the case of endothelin receptors, both arms of G z proteins, ␣ and ␤␥, were suggested to contribute to inhibition of PRL release downstream of VGCI (57). The contribution of G z ␣-mediated attenuation of AC activity in pituitary cells appeared not to be sufficient in dopamine-induced rapid inhibition of PRL release, because such inhibition was preserved in forskolin-treated cells.…”

Multiple Roles of Gi/o Protein‐coupled Receptors in Control of Action Potential Secretion Coupling in Pituitary Lactotrophs

“…For example, the G z signaling pathway probably contributes to the control of PRL release by dopamine when the electrical activity in lactotrophs is stimulated by other factors. Based on the experimental observations outlined above with ET‐1, an elegant theoretical model was developed to describe the complex signaling pathway in these cells, with the main idea that one receptor is coupled to many G proteins 67 . More recent findings further suggested the existence of functional splice forms of ET A receptors, which could add to the remarkable complexity of G protein‐specific coupling 36 …”

Common and diverse elements of ion channels and receptors underlying electrical activity in endocrine pituitary cells

“…I Kir was studied as a regulated channel in models of GHRH stimulation of somatotrophs (Tsaneva-Atanasova et al, 2007), CRH stimulation of corticotrophs (Fletcher et al, 2017; Shorten et al, 2000), and endothelin stimulation of lactotrophs (Bertram et al, 2006) (see Section 3.3.1 for details). Its role in setting rest potential and shaping activity patterns has also been studied in lactotroph (Fletcher et al, 2016) and corticotroph models (Fletcher et al, 2017).…”