Guinea pig GnRH: localization and physiological activity reveal that it, not mammalian GnRH, is the major neuroendocrine form in guinea pigs

The isolation of GnRH cDNA from guinea pig hypothalamus predicted a novel form of GnRH with two unique amino acid substitutions relative to all known forms of this essential decapeptide. The predicted substitution at amino acid 2 in guinea pig (gp) GnRH was particularly intriguing because of the proposed importance of position 2 for binding and activation of the GnRH receptor. In the present study, gpGnRH was synthesized, and a specific antibody was generated and used to assess translation of the gpGnRH transcript. The localization of intensely labeled gpGnRH-positive cell bodies and processes in tissue sections through the preoptic area and hypothalamus argue that gpGnRH is the major neuroendocrine form of GnRH in guinea pigs. Guinea pig GnRH stimulated LH release in guinea pigs and increased LH output from guinea pig pituitary fragments, thus demonstrating biological activity in this species. In contrast, gpGnRH demonstrated little ability to stimulate LH release in rats, a species known to possess the highly conserved mammalian GnRH receptor. These findings suggest that: (1) the amino acid substitutions in gpGnRH impede binding to and/or activation of the mammalian GnRH receptor, and (2) the unique amino acid substitutions in gpGnRH are accompanied by changes in the guinea pig GnRH receptor.