A role for the melanocortin 4 receptor in sexual function

Abstract

By using a combination of genetic, pharmacological, and anatomical approaches, we show that the melanocortin 4 receptor (MC4R), implicated in the control of food intake and energy expenditure, also modulates erectile function and sexual behavior. Evidence supporting this notion is based on several findings: (i) a highly selective nonpeptide MC4R agonist augments erectile activity initiated by electrical stimulation of the cavernous nerve in wild-type but not Mc4r-null mice; (ii) copulatory behavior is enhanced by administration of a selective MC4R agonist and is diminished in mice lacking Mc4r; (iii) reverse transcription (RT)-PCR and non-PCR based methods demonstrate MC4R expression in rat and human penis, and rat spinal cord, hypothalamus, brainstem, pelvic ganglion (major autonomic relay center to the penis), but not in rat primary corpus smooth muscle cavernosum cells; and (iv) in situ hybridization of glans tissue from the human and rat penis reveal MC4R expression in nerve fibers and mechanoreceptors in the glans of the penis. Collectively, these data implicate the MC4R in the modulation of penile erectile function and provide evidence that MC4R-mediated proerectile responses may be activated through neuronal circuitry in spinal cord erectile centers and somatosensory afferent nerve terminals of the penis. Our results provide a basis for the existence of MC4R-controlled neuronal pathways that control sexual function.O ur understanding of the physiology and anatomy of erectile function has advanced considerably in recent years (1-4). Penile erection is a highly coordinated reflex that is subject to modulation at many levels of the neuraxis. Relaxation of smooth muscle fibers of erectile tissue and concomitant dilatation of the arterial supply in the penis produce penile erection. Activation of neurons in the sacral spinal cord triggers activity in the pelvic nerve and, subsequently, the cavernous nerve, which can lead to the release of mediators of vasorelaxation, including nitric oxide. These mediators modulate cyclic nucleotide levels resulting in Ca 2ϩ sequestration and relaxation of smooth muscle fibers of the corpora cavernosa and corpus spongiosum in the shaft of the penis to produce arterial dilatation, engorgement of the penis with blood, and tumescence. Erections can be triggered either by peripheral (tactile) or by central (visual, olfactory, auditory, or imaginative cues) activation of somatic pathways and, as such, are influenced by tonic and phasic activity in the lumbosacral spinal cord and the brain.Five melanocortin heterotrimeric GTP-binding protein (G protein)-coupled receptors have been identified as expressed in different tissues (5, 6). The functional role of each of these five melanocortin receptors is being defined. Rodent and human genetic and pharmacological evidence indicates that activation of melanocortin 4 receptor (MC4R) results in a lean phenotype, whereas inactivation of the MC4R results in obesity (7-10). Recent studies have demonstrated that MTII, a cyclic analogue of ␣-mel...

Preclinical effects of melanocortins in male sexual dysfunction

“…27 However, MC4R has been shown to modulate erectile function and sexual behavior, whereas MC3R has not been shown to have a pro-erectile effect. 28 MC4R is expressed in the rat and human penis, as well as in rat spinal cord, hypothalamus, brainstem and pelvic ganglion, but not in rat corpus cavernosal smooth muscle cells. In mice, administration of an MC4R agonist increased copulation, whereas knockout mice lacking the gene encoding for the receptor showed decreased copulatory behavior.…”

Interactions of Human Melanocortin 4 Receptor with Nonpeptide and Peptide Agonists,

“…Therefore, separate modeling of the isolated peptides and their docking was not required. The following types of constraints were used for the complex: (1) those within the receptor, taken exactly as in the ligand-free form (above); (2) 7 H-bonds between the receptor and ligand identified in the initial model of the complex and during its iterative refinement (see Results); (3) C β -C β upper limit constraints between ligand residues 4-10 and 5-10 of 4.5 and 7.5 Å, respectively, that correspond to 4-10 disulfide and 5-10 lactam bridges in the highly potentα-MSH analogues [Cys 4 9 ), chosen to mimic the bound conformers of the small-molecule agonists determined as described above. Side chain conformers of His 6 (ϰ1 ∼ -60°) and (L, D)Phe 7 (ϰ1 ∼ 180°) were chosen to mimic orientations of D-Tic and D-Phe aromatic rings of THIQ.…”

“…Structures of hMC4R small-molecule agonists. Putative arrangement of the N-terminal fragment (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27) inside the binding pocket of hMC4R, docked similarly to the peptide agonistα-MSH (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13). The N-terminal fragment is shown in the licorice representation colored by element,α-MSH is shown by a thin purple line.…”

“…AGRP acts as an inverse agonist, reducing the elevated basal activity of MC4R (13)(14)(15)(16)(17). Pharmacological studies indicate that activation of the MC4R in rodents modulates erectile function (9). Consequently research efforts have been focused on the development of potent and MC4R-selective agonists as potential anti-obesity drugs or as treatments for sexual dysfunction (18,19).…”

Clinical applications of centrally acting agents in male sexual dysfunction

“…43 The melanocortin 4 receptor, implicated in the control of food intake and energy expenditure, also modulates EF and sexual behavior. 44 As reviewed in this supplement by Shadiack and Althof, these peptides have pronounced effects on the sexual behavior on mice, rats and nonhuman primates.…”