Mechanism of Thyrotropin Releasing Hormone Stimulation of Pituitary Hormone Secretion

Abstract

INTRODUCTIONDuring the past several years, the mechanism of action of thyrotropin-releasing hormone (TRH; thyroliberin) has been studied intensively in GH cells, cloned rat mammotropic tumor cell lines that appear to be valid models for in vitro study of mammotroph fu nction (30,34,48). In this article I review the recent findings (see 26 for previous review) that fo rm the basis for a detailed hypoth esis to explain the transduction of the TRH signal at the cell surface into stimulation of prolactin secretion.It is generally agreed that an elevation of cyt9plasmic free calcium ion concentration ([Ca2+]i) serves to couple, at least in part, the binding of many hormones and neurotransmitters to plasma membrane receptors with the stimulation of a variety of cellular processes (51). The elevation of [ Ca2+]i induced by these stimulants may be caused by mobilization (or redistribution) of intracellular calcium, or by enhancement of influx of extracellular Ca2+ , or both (17). It has been demonstrated that in some of these cells a very rapid effect after stimulant-receptor interaction is enhanced hydrolysis of phosphatidylin ositoI4,5-bisphosphate [PtdIns( 4,5)P 2 ] by a phospholipase C (or phosphodies terase) to yield 1 ,2 -diacylglycerol (DG) and inositoltrisphosphate (InsP3) (18). Furthermore, it has been proposed that both DG (50) and InsP3 (11) may serve as intracellular mediators (or second messengers) to transduce and amplify the signal, leading to stimulation of the physiologic response(s). DG appears to 515 0066-4278/86/0315-0515$02.00Annu. Rev. Physiol. 1986.48:515-526. Downloaded from www.annualreviews.org Access provided by University of California -Davis on 02/04/15. For personal use only. Quick links to online content Further ANNUAL REVIEWS 516 GERSHENGORN exert its effects by enhancing the activity of a Ca 2 + -and phospholipid dependent protein kinase (protein kinase C) by an action that does not depend on an elevation of [Ca2+];. InsP3 appears to act to mobilize calcium from an intracellular pool to elevate [Ca2+]i' In addition, influx of extracellular calcium may be enhanced by hormones and neurotransmitters to elevate [Ca2+]i' The elevation of [Ca2+]; may activate a Ca2+ -and calmodulin-dependent protein kinase(s) and, perhaps, other processes. It appears that this generalized schema of signal transduction by separate but converging pathways involving Ca2+ �nd lipid messengers may describe the mechanism of TRH stimulation of prolactin secretion. TRH AND PHOSPHOINOSITIDESIn this section I present evidence that strongly supports the concept that in GH cells TRH acts to stimulate the hydrolysis of Ptdlns(4,5)P 2 by a phospholipase C to yield InsP 3 and DG, and that this action may be the initial step in the sequence of intracellular events leading to prolactin secretion. The studies I emphasize have been performed in cells prelabeled with precursors to isotopic equilibrium in order to facilitate measurement of changes in the cellular content of even minor substances, such as PtdIns(4, 5)P2 and InsP3. ...

Thyrotropin-Releasing Hormone Receptor Type 1 (TRH-R1), not TRH-R2, Primarily Mediates Taltirelin Actions in the CNS of Mice

“…We compared the effects of TAL and TRH in competition binding assays with [ 3 H]MeTRH, a high affinity agonist for both TRH receptors (Sun et al, 2003), and on two early steps in signal transduction by TRH receptors (Gershengorn, 1986), inositol-1,4,5-trisphosphate production (by measuring its degradation product inositolmonophosphate) and intracellular calcium release (Figure 1 and (IC 50 ) to TRH-R1 was 520 nM for TAL and 15 nM for TRH. For TRH-R2, the IC 50 s were 110 nM for TAL and 5.4 nM for TRH.…”

Potentially predictive and manipulable blood serum correlates of aging in the healthy human male: Progressive decreases in bioavailable testosterone, dehydroepiandrosterone sulfate, and the ratio of insulin-like growth factor 1 to growth hormone

“…However, the r values of IGF-1͞GH with BT (0.38) and DHEAS (0.51) were lower than that of BT with DHEAS (0.68). Age-related decrement in IGF-1͞GH may be related to a progressive decrease in production of hypothalamic thyrotropin-releasing hormone and the consequential dysregulation of the hypothalamo-pituitary-thyroid axis (37)(38)(39).…”

Regulation of L‐Type Calcium Channels in GH4 Cells via A1 Adenosine Receptors

“…Thyrotropin-releasing hormone (TRH) elicits an inositol phosphate-gated release of calcium from intracellular stores that leads to calcium-dependent inactivation of L-type channels (Gershengorn, 1986;Kramer et al, 1991Kramer et al, , 1994Wagner et al, 1993;Mantegazza et al, 1995). Although activation of human dopamine D2 and D4 receptors, transfected in GH4 cells, inhibits dihydropyridine-sensitive calcium currents, the mechanism by which D4 receptors couple to these calcium currents is distinct from that of thyrotropin-induced calcium mobilization (Seabrook et al, 1994).…”