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Endocrinology and Reproduction Research Branch National Institute of Child Health and Human Development National Institutes of Health Bethesda, Maryland 20892
The mammalian GnRH receptor is an atypical G
protein-coupled receptor which lacks the C-terminal cytoplasmic tail
that is present in all other seven-transmembrane domain receptors.
The mouse and rat GnRH receptors contain 327 amino acids, whereas
human, sheep, and bovine receptors have an additional residue in the
second extracellular loop at position 191. Another notable species
difference is that human receptors undergo agonist-induced
internalization much more rapidly than the mouse receptor. In this
report, the role of the additional amino acid (Lys191) in GnRH receptor
function was studied in transiently expressed mutant and wild-type
human and mouse GnRH receptors. Deletion of Lys191 from the human GnRH
receptor caused a 4-fold increase in receptor expression in COS-1 and
HEK 293 cells and a modest increase in binding affinity. The magnitude
of the agonist-induced inositol phosphate response mediated by the
K191 human receptor was similar to that of the wild-type receptor,
but the EC50 was decreased by about 5-fold. In
addition, the rate of internalization of the K191 human receptor was
significantly reduced and was similar to that of the mouse receptor. In
contrast to these effects of deletion of Lys191, its replacement by
Arg, Glu, Gln, or Ala caused no significant change in receptor
expression or function. These findings demonstrate that a specific
residue in the extracellular region of the human GnRH receptor is
a significant determinant of receptor expression, agonist-induced
activation, and internalization.
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