ART (Protein Product of Agouti-Related Transcript) as an Antagonist of MC-3 and MC-4 Receptors

Fong, Tung M.; Mao, Catherine D.; MacNeil, Tanya; Kalyani, Rubana N.; Smith, T. D.; Weinberg, David H.; Tota, Michael R.; Ploeg, Lex H.T. Van der

doi:10.1006/bbrc.1997.7200

Cited by 209 publications

(132 citation statements)

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“…In mammals, AgRP is a selective antagonist of the melanocortin receptors MC3R and MC4R, expressed primarily in the CNS (18,21). Using HEK293 cells expressing recombinant zebrafish melanocortin receptors, we showed previously that mouse AgRP can competitively decrease α-MSH-mediated cAMP production, with high efficacy at MC1R, MC3R, and MC4R (24).…”

Section: Resultsmentioning

confidence: 99%

“…The two agouti proteins found in mammals, ASP and AgRP, acting as high-affinity endogenous antagonists of the melanocortin family of receptors (18,20,21), have been demonstrated to regulate the eumelanin-pheomelanin switch in mammalian pelage and long-term energy homeostasis, respectively. A gene encoding a third agouti protein, AgRP2, has been identified now in several fish species, including zebrafish, trout, Tetraodon, and Torafugu (22), and thus far seems unique to teleost fishes.…”

Section: Discussionmentioning

confidence: 99%

“…The agouti proteins are small secreted molecules (16)(17)(18)(19)) that act as endogenous antagonists of the melanocortin receptors (18,20,21), a family of G protein-coupled receptors. Two agouti genes are found in mammals, agouti (ASP) (16,17), which regulates the eumelanin-pheomelanin switch in mammalian pelage, and agoutirelated protein (AgRP), which is expressed in the CNS and regulates energy homeostasis (18,19).…”

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confidence: 99%

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Pineal-specific agouti protein regulates teleost background adaptation

Zhang

Song

Thompson

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Background adaptation is used by teleosts as one of a variety of camouflage mechanisms for avoidance of predation. Background adaptation is known to involve light sensing by the retina and subsequent regulation of melanophore dispersion or contraction in melanocytes, mediated by α-melanocyte-stimulating hormone and melanin-concentrating hormone, respectively. Here, we demonstrate that an agouti gene unique to teleosts, agrp2, is specifically expressed in the pineal and is required for up-regulation of hypothalamic pmch and pmchl mRNA and melanosome contraction in dermal melanocytes in response to a white background. floating head, a mutant with defective pineal development, exhibits defective up-regulation of mch mRNAs by white background, whereas nrc, a blind mutant, exhibits a normal response. These studies identify a role for the pineal in background adaptation in teleosts, a unique physiological function for the agouti family of proteins, and define a neuroendocrine axis by which environmental background regulates pigmentation.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Pineal-specific agouti protein regulates teleost background adaptation

Zhang

Song

Thompson

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…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)(8)(9)(10). Recent studies have demonstrated that MTII, a cyclic analogue of ␣-melanocyte stimulating hormone (␣-MSH) and a subnanomolar agonist of the MC1R, MC3R, MC4R, and MC5R can stimulate nonpainful intermittent penile erections in man (11).…”

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confidence: 99%

A role for the melanocortin 4 receptor in sexual function

Ploeg

Martin

Howard

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

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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...

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“…Both the fulllength protein as well as several fragments containing the cysteine rich C-terminal part of the protein function as competitive antagonists at the melanocortin receptors (MCRs) 3 and 4 [1,[11][12][13][14][15]. More recently, it has been demonstrated that the AgRP 83-132 fragment, and also the smaller AgRP 87-120, functions as an inverse agonist at the hMC3R and hMC4R, suppressing the constitutive activation of adenylate cyclase by these receptors [16][17][18].…”

Section: Introductionmentioning

confidence: 99%

Functional analysis of the Ala67Thr polymorphism in agouti related protein associated with anorexia nervosa and leanness

Rijke

Jackson

Garner

et al. 2005

Biochemical Pharmacology

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AgRP is a neuropeptide that stimulates food intake through inhibition of central melanocortin receptors (MCRs). In humans, the nonconservative amino acid substitution Alanine (Ala) 67 Threonine (Thr) has been associated with Anorexia Nervosa and with leanness. In the present study, the cellular distribution, processing and in vitro and in vivo activities of Ala67 and Thr67 AgRP were investigated. Western blots of media and lysates of BHK cells stably transfected with Ala67 or Thr67 expression constructs showed identical AgRP bands. Both Ala67 and Thr67 AgRP colocalised with the Golgi apparatus, but not with the ER or lysosomes when expressed in Att20 D16V cells. Also, no differences were observed between the potencies of bacterially expressed Ala67 and Thr67 AgRP to stimulate MC4R in a reporter gene assay or inhibit food intake in rats. Taken together, no evidence was found for a functional defect of Thr67 AgRP related to MC4R interactions. #

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ART (Protein Product of Agouti-Related Transcript) as an Antagonist of MC-3 and MC-4 Receptors

Cited by 209 publications

References 10 publications

Pineal-specific agouti protein regulates teleost background adaptation

Pineal-specific agouti protein regulates teleost background adaptation

A role for the melanocortin 4 receptor in sexual function

Functional analysis of the Ala67Thr polymorphism in agouti related protein associated with anorexia nervosa and leanness

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