Alterations of Adenylyl Cyclase Sensitivity to Hormones in the Brain, Myocardium and Testes of Rats Immunized with BSA-Conjugated Peptide 269-280 of the Type 3 Melanocortin Receptor

作者：Shpakov A O^*; Derkach K V; Zharova O A; Shpakova E A; Bondareva V M

来源：Biologicheskie Membrany, 2015, 32(1): 20-32.

DOI：10.7868/S0233475515010077

• adenylyl cyclase
• beta-adrenergic agonist
• type 3 melanocortin receptor
• melanocyte-stimulating hormone
• brain

Binding of the type 3 melanocortin receptor (M3R) functionally coupled to G(s)-proteins with alpha-melanocyte-stimulating hormone (alpha-MSH) or M3R agonist gamma-MSH results in activation of adenylyl cyclase (AC) in the brain, which is responsible for the M3R-mediated regulation of physiological and biochemical processes in the CNS and in the periphery Decrease in the activity of M3R leads to changes in the energy metabolism, metabolic syndrome, and abnormalities in the nervous and cardiovascular systems. However, the molecular mechanisms of these alterations and the role of the adenylyl cyclase signaling system (ACSS) in them are still poorly understood. The aim of this work was to study the effect of long-term (13 months, 8 injections) immunization of male rats with BSA-conjugated peptide A-[PTNPYCICTTAH(269-280)]-A(A-[269-280]-A) corresponding to the third extracellular loop of rat M3R on the functional-activity of ACSS in the brain, testis and myocardium of rats and on its regulation by neurotransmitters and hormones. At the end of the experiment the body weight of animals was lowered, fat mass was increased and dyslipidemia was observed; besides sensitivity to insulin was reduced, despite an increase in the insulin secretion in response to glucose loading. In the brain of immunized rats the AC stimulating effects of gamma-MSH, norepinephrine, serotonin, and PACAP-38 were reduced, the stimulating effect of dopamine was increased and the AC inhibitory effects of serotonin and 5-nonyloxytryptamine, an agonist of subtype 1B/1D 5-hydroxytryptamine receptor, were amplified, while the AC effects of M3R/M4R-agonist a-MSH and M4R-agonist THIQ did not change. In the myocardial membranes the increase of AC stimulation by agonists of beta(3)-adrenergic receptor (beta(3)-AR) and the decrease of the AC stimulating effects of beta(1)- and beta(2)-agonists, as well as the weakening of the AC effect of relaxin were found. In the testicular membranes the AC stimulating effects of chorionic gonadotropin and PACAP-38, and GppNHp, non-hydrolysable GTP analog were decreased. These data indicate that the weakening of M3R signaling leads to significant changes in the sensitivity of ACSS in the brain, myocardium and testis to hormones that play a key role in the functioning of the nervous, cardiovascular and reproductive systems, and these changes were characterized by hormone and receptor specificity. Identification of the disturbances in ACSS is one of the approaches to study the etiology and pathogenesis of the diseases associated with inhibition of M3R-melanocortin signaling system in the brain.

• 出版日期2015-2