Cholera toxin and pertussis toxin provoke differential effects on luteinizing hormone release, inositol phosphate production, and gonadotropin-releasing hormone (GnRH) receptor binding in the gonadotrope: evidence for multiple guanyl nucleotide binding proteins in GnRH action.
A growing body of evidence suggests a role for guanyl nucleotide binding proteins (G proteins) in GnRH action. G protein activation provokes LH release, inositol phosphate (IP) production, decreased gonadotrope responsiveness to GnRH, increased gonadotrope responsiveness to the calcium ionophore A23187, and decreased GnRH receptor binding. The specific G proteins involved in these actions, however, are not known. This study uses pertussis toxin (PTX) and cholera toxin (CTX), which affect the activity of a number of G proteins by ADP ribosylation of a Cys or an Arg residue, respectively, of the alpha-subunit. Although not an effective LH secretagogue in itself, CTX enhanced GnRH-, NaF-, and A23187-stimulated LH release after an 18-h pretreatment period. CTX pretreatment did not affect GnRH- or NaF-stimulated IP production. Conversely, 18 h pretreatment with PTX reduced GnRH- and NaF-provoked IP production compared to control values, but did not affect LH release. In addition, pretreatment with either CTX, PTX, or Bt2cAMP provoked a decrease in GnRH receptor binding compared to control. The results of this study suggest that: 1) GnRH stimulates IP production, but not LH release, through a PTX-sensitive G protein; 2) A distinct CTX-sensitive G protein appears to provoke gonadotrope sensitization by stimulating an increase in intracellular cAMP levels; and 3) there appears to be a distinct G protein, insensitive to PTX and CTX, capable of mediating LH release independent of IP production and cAMP.
Department of Pharmacology, University of Iowa College of Medicine, Iowa City 52242-1109.
B E
BE
Hawes
S
S
Barnes
P M
PM
Conn
D000818:Animals; D003994:Bucladesine / Q000494:pharmacology; D000001:Calcimycin / Q000494:pharmacology; D002772:Cholera Toxin / Q000494:pharmacology*; D005260:Female; D019204:GTP-Binding Proteins / Q000378:metabolism; D007987:Gonadotropin-Releasing Hormone / Q000494:pharmacology; D007295:Inositol Phosphates / Q000096:biosynthesis*; D007986:Luteinizing Hormone / Q000378:metabolism*; D037342:Pertussis Toxin; D010902:Pituitary Gland / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011966:Receptors, LHRH / Q000378:metabolism*; D012969:Sodium Fluoride / Q000494:pharmacology; D010566:Virulence Factors, Bordetella / Q000494:pharmacology*
D007295:Inositol Phosphates; D011966:Receptors, LHRH; D010566:Virulence Factors, Bordetella; D007987:Gonadotropin-Releasing Hormone; D000001:Calcimycin; D003994:Bucladesine; D012969:Sodium Fluoride; D007986:Luteinizing Hormone; D002772:Cholera Toxin; D037342:Pertussis Toxin; D019204:GTP-Binding Proteins