Alterations in adenylyl cyclase sensitivity to hormones in the brain, myocardium, and testes of rats immunized with BSA-conjugated peptide 269–280 of type 3 melanocortin receptor

Abstract

Binding of the type 3 melanocortin receptors (M3R) functionally coupled to Gs proteins with α-melanocyte-stimulating hormone (α-MSH) or M3R agonist γ-MSH results in the activation of adenylyl cyclase (AC) in the brain, which is responsible for the M3R-mediated regulation of physiological and biochemical processes in the central and peripheral nervous systems. A decrease in the M3R activity leads to energy metabolism disorders, metabolic syndrome, and functional disturbances of the nervous and cardiovascular systems. However, molecular mechanisms of these alterations and the role of the adenylyl cyclase signaling system (ACSS) are yet poorly understood. The aim of this work was to study the effects of a long-term (13 months, 8 injections) immunization of male rats with BSA-conjugated peptide A-[PTNPYCICTTAH269–280]-A (A-[269–280]-A), corresponding to the third extracellular loop of rat M3R, on the functional activity of ACSS and its regulation by neurotransmitters and hormones in rat brain, testes, and myocardium. At the end of the experiment, the body weight of animals decreased, the specific mass of adipose tissue increased, dyslipidemia was observed, and the sensitivity to insulin was reduced in spite of the increase in its secretion in response to a glycemic load. In the brain of immunized rats, the AC-stimulating effects of γ-MSH, noradrenaline, serotonin and PACAP-38 decreased, the stimulating effect of dopamine and AC-inhibiting effects of serotonin and 5-nonyloxytryptamine (an agonist of 5-hydroxytryptamine receptor (5-HTR) of the 1B/1D subtype) increased, while the effects of the M3R/M4R agonist α-MSH and the M4R agonist THIQ remained unchanged. In myocardial membranes, stimulation of AC by the agonists of β3-adrenergic receptors (β3-AR) was enhanced, while the AC-stimulating effects of β1- and β2-agonists were attenuated and the AC effect of relaxin weakened. In testicular membranes, the AC-stimulating effects of chorionic gonadotropin and PACAP-38 decreased, as well as the effect of GppNHp (non-hydrolysable GTP analog). These data indicate that the attenuation of the M3R signaling leads to considerable alterations in the ACSS sensitivity to the hormones playing a key role in the functioning of the nervous, cardiovascular and reproductive systems. The alterations in the ACSS sensitivity observed in brain, myocardium and testes are characterized by hormonal and receptor specificity. Identification of ACSS disorders is one of the approaches to studying etiology and pathogenesis of diseases associated with inhibition of M3R-melanocortin signaling system of the brain.