Activation of the cAMP pathway by variant human MC1R alleles expressed in HEK and in melanoma cells.
Alpha-melanocyte-stimulating hormone (alpha-MSH) activates the melanocortin-1 receptor (MC1R) on melanocytes to promote a switch from red/yellow pheomelanin synthesis to darker eumelanins via positive coupling to adenylate cyclase. The human MC1R locus is highly polymorphic with the specific variants associated with red hair and fair skin (RHC phenotype) postulated to be loss-of-function receptors. We have examined the ability of MC1R variants to activate the cAMP pathway in stably transfected HEK293 cells. The RHC associated variants, Arg151Cys, Arg160Trp and Asp294His, demonstrated agonist-mediated increases in cAMP and phosphorylation of cAMP-responsive element-binding protein (CREB). Whereas the Asp294His variant showed severely impaired functional responses, the Arg151Cys and Arg160Trp variants retained considerable signaling capacity. Melanoma cells homozygous for either the Arg151Cys variant or consensus sequence both elicited CREB phosphorylation in response to alpha-MSH in the presence of IBMX. The common RHC alleles, Arg151Cys, Arg160Trp and Asp294His, are neither complete loss-of-function receptors nor are they functionally equivalent.
Melanogenix Group, Institute for Molecular Bioscience, University of Queensland, Brisbane, Qld. 4072, Australia.
Richard A
RA
Newton
Sonia E
SE
Smit
Christopher C
CC
Barnes
Julie
J
Pedley
Peter G
PG
Parsons
Richard A
RA
Sturm
D000483:Alleles; D002460:Cell Line; D045744:Cell Line, Tumor; D000242:Cyclic AMP / Q000378:metabolism* / Q000502:physiology; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D005786:Gene Expression Regulation / Q000502:physiology*; D014644:Genetic Variation; D006801:Humans; D008545:Melanoma / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation; D044102:Receptor, Melanocortin, Type 1 / Q000096:biosynthesis* / Q000235:genetics* / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics*
D017362:Cyclic AMP Response Element-Binding Protein; D044102:Receptor, Melanocortin, Type 1; D000242:Cyclic AMP