Identification and Isolation of Components from the Venom of the Snail Conus distans which Target the Somatostatin Receptor

Abstract

This study reports two partially isolated agonists or antagonists for somatostatin from the toxin of the marine snail, Conus distans. Somatostatin is a widely distributed hormone that has five receptor Subtypes, and, to date, it does not have any known antagonists or selective agonists for all receptor Subtypes. (Reisine and Bell, 1995) The venoms from thirteen species of Cone snails were examined in an assay for somatostatin receptor-site competition using radiolabeled 125 I-Tyr 11-somatostatin and a whole rat brain tissue preparation. Our results show that the venom from Conus distans completely inhibits binding of somatostatin. The venoms from other Cone snail species gave only partial or no inhibition of selective somatostatin binding in this assay. A series of sequential separations by reverse-phase HPLC, monitored by somatostatin binding assays were then used to partially purify the active material in the Conus distans venom. A procedure to differentiate somatostatin agonist or antagonist activity was developed in this project based on the agonist-stimulated GTP[y-35 S] binding assay in membranes (Sim et aI., 1995). To employ this assay, we first established that somatostatin stimulates GTP binding to the G-protein in this assay. Somatostatin had not previously been shown to stimulate GTP binding in this assay. Future work using this assay will be necessary to determine if the active material from the Conus distans venom is an agonist or antagonist of somatostatin stimulation of GTP binding to G-proteins. Development of selective somatostatin agonists and antagonists will be useful in the characterization of somatostatin receptors and may be clinically useful in the treatment of central nervous system (CNS) abnormalities related to somatostatin such as motor disorders, Alzheimer's disease, and epilepsy (Epelbaum, 1986; Raynor and Reisine, 1992; Reisine and Bell, 1995).