Orexins/hypocretins Acting at Gi Protein-coupled OX 2 Receptors Inhibit Cyclic AMP Synthesis in the Primary Neuronal Cultures

Overview

Journal J Mol Neurosci

Specialties Molecular Biology
Neurology

Date 2011 May 7

PMID 21547533

Citations 16

Authors

Anna Urbanska

Paulina Sokolowska

Agata Woldan-Tambor

Kaja Bieganska

Britta Brix

Olaf Johren

Magdalena Namiecinska

Jolanta Barbara Zawilska

Affiliations

Soon will be listed here.

Abstract

Orexins A and B are newly discovered neuropeptides with pleiotropic activity. They signal through two G protein-coupled receptors: OX(1) and OX(2). In this study, we examined the expression of orexin receptors and effects of the receptors' activation on cyclic AMP formation in the primary neuronal cell cultures from rat cerebral cortex. Both types of orexin receptors were expressed in rat cortical neurons; the level of OX(2)R was markedly higher compared to OX(1)R. Orexin A (an agonist of OX(1)R and OX(2)R) and [Ala(11)-D-Leu(15)]orexin B (a selective agonist of OX(2)R) did not affect basal cyclic AMP formation in the primary neuronal cell cultures. Both peptides (0.001-1 μM) inhibited, in a concentration-dependent manner and IC(50) values in low nanomolar range, the increase in the nucleotide production evoked by forskolin (1 μM; a direct activator of adenylyl cyclase), pituitary adenylate cyclase-activating polypeptide (PACAP27; 0.1 μM), and vasoactive intestinal peptide (VIP; 3 μM). Effects of orexin A on forskolin-, PACAP27-, and VIP-stimulated cyclic AMP synthesis were blocked by TCS OX2 29 (a selective antagonist of OX(2)R), and unaffected by SB 408124 (a selective antagonist of OX(1)R). Pretreatment of neuronal cell cultures with pertussis toxin (PTX) abolished the inhibitory action of orexin A on forskolin- and PACAP-stimulated cyclic AMP accumulation. It is suggested that in cultured rat cortical neurons orexins, acting at OX(2) receptors coupled to PTX-sensitive G(i) protein, inhibit cyclic AMP synthesis.

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