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₁-Adrenergic Receptors Mediate LH-Releasing Hormone Secretion through Phospholipases C and A₂ in Immortalized Hypothalamic Neurons

Laboratory of Signal Transduction, National Institute of Environmental Health Sciences (S.M.K., M.S., S.F., C.M.R., S.S.), Research Triangle Park, North Carolina 27709; and Department of Psychiatry and Behavioral Sciences, Duke University Medical Center (G.X.L., W.X., K.W.D., S.C., W.C.W.), Durham, North Carolina 27710

Address all correspondence and requests for reprints to: Dr. William C. Wetsel, Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Box 3497, 028 CARL Building, Durham, North Carolina 27710. E-mail: wetse001{at}mc.duke.edu

Norepinephrine has long been known to stimulate the pulsatile and preovulatory release of LH-releasing hormone (LHRH). In vivo and in vitro studies indicate that these effects are mediated primarily through ₁-adrenergic receptors (₁-ARs). With the immortalized hypothalamic LHRH neurons, we have found that ₁-adrenergic agents directly stimulate the secretion of LHRH in a dose-dependent manner. Ligand binding and RNA studies demonstrate that the GT1 cells contain both _1A- and _1B-ARs. Competition binding experiments show that approximately 75% of the binding is due to _1B-ARs; the remainder is made up of _1A-ARs. Receptor activation leads to stimulation of PLC. PLCß1 and PLCß3 are expressed in GT1 neurons, and these PLCs are probably responsible for the release of diacylglycerol and IP as well as the increase in intracellular calcium. The mobilization of cytoplasmic calcium is sufficient to stimulate cytosolic PLA₂ (cPLA₂) and release arachidonic acid. A dissection of the contributions of the phospholipases to LHRH secretion suggests that cPLA₂ acts downstream of PLC and that it significantly augments the PLC-stimulated LHRH secretory response. Inasmuch as the ₁-ARs are known to play a critical role in LHRH physiology, we propose that both PLC and cPLA₂ are critical in regulating and amplifying LHRH release.

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