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, 99 (17), 11381-6

A Role for the Melanocortin 4 Receptor in Sexual Function

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A Role for the Melanocortin 4 Receptor in Sexual Function

Lex H T Van der Ploeg et al. Proc Natl Acad Sci U S A.

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 non-peptide 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.

Figures

Fig 1.
Fig 1.
Effects of sildenafil citrate (A) or THIQ MC4R agonist (C) in the mouse cavernous nerve-stimulated model of erectile function. Cavernous nerve stimulation (4.0 v, 16 Hz, 1 ms, for 30 s) was conducted in anesthetized male C57BL/6J mice [n = 6; Mc4r knock-out (−/−) mice were backcrossed six generations with C57BL/6J mice]. Mice were instrumented with corpus cavernosum, carotid artery, and jugular vein catheters for measurement of ICP, MAP, and i.v. compound administration (1 mg/kg for sildenafil, 10 mg/kg for MC4R agonist as a bolus), respectively. The ratio of ICP/MAP (to normalize for any effects on blood pressure) was calculated at −10 min (baseline) followed by 15 and 45 min postdose (sildenafil) or/and 15 min postdose (THIQ); the area under the curve during the 60 s of stimulation was then determined. *, P < 0.05. (B) MCR selectivity profile of THIQ MC4R agonist. EC50 values were determined in a functional activation assay in whole cells measuring cAMP production from cell lines expressing the appropriate MCR (rat Mc3r, 4r, 5r, murine Mc2r, 4r, and human MC1R; species specificity, affecting compound selectivity, has not been observed). The chemical structure of the MC4R agonist is shown.
Fig 2.
Fig 2.
(A and B) Copulatory behavior of male Mc4r−/− mice and wild-type mice treated with the THIQ MC4R agonist. (A) Male wild-type and Mc4r−/− mice (n = 10; strain C57Bl6J/129SJl) were paired with estrous females for 45 min. *, P < 0.05. (B) Male wild-type mice (n = 7 or 8; strain C57Bl6J) were injected i.p. with either vehicle, the nonselective 5HT2b, 2c agonist mCPP (0.75 mg/kg), or the THIQ MC4R agonist (2.5 mg/kg) 15 min before pairing them with an estrous female. *, P < 0.05 (please note that baseline values for mounting and intromission latencies differ between distinct genetic backgrounds; compare A and B with C and D).
Fig 3.
Fig 3.
Microphysiometric characterization of rat corpus cavernosum cells. Primary cultures of rat smooth muscle cells from rat corpus cavernosum (and CHO cells stably expressing the rat MC4R) were tested for ligand-stimulated metabolic activation. The acidification rate (μVolt/s) was monitored during the addition of the indicated concentrations of the melanocortin agonists MTII, α-NDP-MSH, and MC4R agonist. Endothelin-1, an agonist of ETA receptors present on smooth muscle cells, was used as a control. The values represent the rate of acidification compared with the unstimulated basal rate and are representative of three independent experiments.
Fig 4.
Fig 4.
(A) RNase A protection assay (RPA) of rat MC4R in penile tissues. Poly(A)+ RNA (6 μg) was hybridized with a rat MC4R cDNA probe (second intracellular loop to mid transmembrane-6) that, upon RNase digestion, would result in a radiolabeled fragment of 313 nucleotides, revealed by denaturing PAGE and autoradiography (as detailed in Materials and Methods). An internal standard rat MC4R fragment of 240 nucleotides is shown. (B) Binding of [125I]MTII to rat penile membranes. Inhibition of [125I]MTII binding by MTII and the THIQ MC4R agonist was performed by using 70 pM radiolabeled MTII for 70 min at 20°C; the results are expressed as percent of [125I]MTII specifically bound. IC50 values for MTII and MC4R agonist were 1.5 and 11 nM, respectively (n = 3 experiments).
Fig 5.
Fig 5.
MC4R expression in nerve fibers, nerve endings, and sensory corpuscles of the human glans penis. In situ hybridization was carried out by using riboprobes for human (ac) or rat (d) MC4R. (a) MC4R mRNA in the human penis corpus spongiosum (CS) is seen in nerve fibers (shown in red); nuclei are seen in blue. Sense control probe produced no specific signal (Inset). (b) MC4R colocalized with the nerve fiber marker PGP9.5 in a CS mechanoreceptor. MC4R signal is shown in green, PGP9.5 immunoreactivity in red, and colocalization in yellow. (c) MC4R in situ hybridization signal in an encapsulated sensory corpuscle of the CS of the human glans penis. MC4R is shown in red, nuclei in blue. Layers of the human glans penis are labeled as epithelium (Epi), lamina propria (LP), and CS. High magnification view (Inset) suggests that this is a Pacinian-lamellated corpuscle. (d) MC4R localization in a Meissner-encapsulated corpuscle found in the LP of the rat glans penis. MC4R signal is shown in red, nuclei in blue. (Bars = 20 μm.)
Fig 6.
Fig 6.
The neural control of penile erection (2) summarizing putative sites of erectogenesis of MC4R agonists (modified from ref. 41). *, distribution of MC4R.

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