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γ‐MSH Peptides in the Pituitary
Author(s) -
DENEF C.,
LU J.,
SWINNEN E.
Publication year - 2003
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1111/j.1749-6632.2003.tb03171.x
Subject(s) - melanocortin , agonist , endocrinology , gtpgammas , receptor , medicine , chemistry , melanocortin 3 receptor , intracellular , biology , melanocortin receptor , biochemistry
A bstract : The melanocortin (MC) γ3‐MSH is believed to signal through the MC3 receptor. We showed that it induces a sustained increase in intracellular free calcium levels ([Ca 2+ ] i ) in a subpopulation of pituitary cells. Most of the cells responding to γ3‐MSH express more than one pituitary hormone mRNA. The effect of γ3‐MSH is blocked by SHU9119, a MC3R and MC4R antagonist, in only 50% of the responsive cells, suggesting that in half of these cells the mediating receptor is not the MC3R. Low picomolar doses of γ3‐MSH increase [Ca 2+ ] i in the growth hormone (GH)‐ and prolactin (PRL)‐secreting GH3 cell line. γ2‐MSH and α‐MSH display a similar effect. SHU9119 does not affect the γ3‐MSH‐induced [Ca 2+ ] i response. MTII, a potent synthetic agonist of the MC3R, MC4R, and MC5R, also shows no or low potency in increasing [Ca 2+ ] i . By means of RT‐PCR, the mRNA of the MC2R, MC3R, and MC4R receptors is undetectable. Experiments testing γ2‐MSH analogues with single alanine replacements show that, unlike the classic MCRs, the His 5 ‐Phe 6 ‐Arg 7 ‐Trp 8 sequence in γ2‐MSH is not a core sequence for activating the γ‐MSH receptor in GH3 cells, whereas Met 3 is essential. Low nanomolar doses of γ‐MSH increase intracellular cAMP levels. Blockade of protein kinase A abolishes the [Ca 2+ ] i responses to γ3‐MSH. γ2‐MSH increases binding of [S 35 ]GTPγS to membrane preparations of GH3 cells. The pharmacological characteristics of γ‐MSH peptides and analogues on [Ca 2+ ] i and the signal‐transduction pathways present strong evidence for the expression of a hitherto uncharacterized γ‐MSH receptor in GH3 cells, belonging to the G protein‐coupled receptor family.