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Identification of a Pituitary Growth Hormone-Releasing Peptide (GHRP) Receptor Subtype by Photoaffinity Labeling

Faculty of Pharmacy (H.O., N.McN.) and Ste-Justine Hospital (R.C.), University of Montréal, Montréal, Canada; Department of Pharmacology (E.E.), University of Sherbrooke, Sherbrooke, Canada; Europeptides (R.D.), Argenteuil, France; Department of Pharmacology (V.L.), University of Milan, Milan, Italy; Department of Internal Medecine (E.G.) and Department of Anatomy (G.M.), University of Turin, Turin, Italy; Pharmacia & Upjohn (M.B., M.N.), Stockholm, Sweden

Address all correspondence and requests for reprints to: Dr. Huy Ong, Université de Montréal, Faculté de Pharmacie, C.P. 6128, Succ. Centre-Ville, Montréal, Québec H3C 3J7, Canada.

Hexarelin, an analogue of GHRP-6, in which D-Tryptophan has been replaced by its 2-methyl derivative, is known to release growth hormone (GH) in vivo and in vitro by direct action on receptors present in anterior pituitary cells. Measurement of second messengers (c-AMP, Ca⁺⁺, IP₃) upon somatotrophs stimulation, suggests the existence of more than one GHRP receptor subtype. In order to document such an hypothesis, we have used a new photoactivatable derivative of Hexarelin, Tyr-Bpa-Ala-Hexarelin. This derivative was shown to be fully active in the release of GH in vivo with neonate rats. Using this photoactivatable ligand, we have specifically labeled a protein with an apparent M_r of 57 000 in human, bovine and porcine anterior pituitary membranes. Hexarelin and the spiroindoline sulfonamide MK-0677 displaced the M_r -57 000 photolabeled band with an apparent ED₅₀ of 6x10^-7 M and 2x10^-5 M respectively. Taking into account the high efficiency (>60%) of covalent incorporation of the Bpa residue, this photoactivatable Hexarelin derivative has allowed the identification of a pituitary GHRP receptor subtype, which is apparently distinct from the recently cloned GH secretagogue receptor.

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