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Gonadotropin and Gonadal Steroid Release in Response to a Gonadotropin-Releasing Hormone Agonist in G_q and G₁₁ Knockout Mice¹

Oregon Regional Primate Research Center (D.S., J.A.J., P.M.C.), Divisions of Neuroscience and Reproductive Science, Beaverton, Oregon 97006; Oregon Health Sciences University (D.S., P.M.C.), Department of Physiology and Pharmacology, Portland, Oregon 97201; University of Wyoming (T.J.), Department of Molecular Biology, Laramie, Wyoming 82071; University of Texas Southwestern Medical Center (T.M.W.), Department of Pharmacology, Dallas, Texas 75235; and California Institute of Technology (S.O.), Pasadena, California 91125

Address all correspondence and requests for reprints to: P. Michael Conn, Oregon Regional Primate Research Center, 505 N.W. 185th Avenue, Beaverton, Oregon 97006-3499.

In this study, we used mice lacking the G₁₁ [G₁₁ knockout (KO)] or G_q gene (G_q KO) to examine LH release in response to a metabolically stable GnRH agonist (Buserelin). Mice homozygous for the absence of G₁₁ and G_q appear to breed normally. Treatment of (5 wk old) female KO mice with the GnRH agonist Buserelin (2 µg/100 µl, sc) resulted in a rapid increase of serum LH levels (reaching 328 ± 58 pg/25 µl for G₁₁ KO; 739 ± 95 pg/25 µl for G_q KO) at 75 min. Similar treatment of the control strain, 129SvEvTacfBr for G₁₁ KO or the heterozygous mice for G_q KO, resulted in an increase in serum LH levels (428 ± 57 pg/25 µl for G₁₁ KO; 884 ± 31 pg/25 µl for G_q KO) at 75 min. Both G₁₁ KO and G_q KO male mice released LH in response to Buserelin (2 µg/100 µl of vehicle; 363 ± 53 pg/25 µl and 749 ± 50 pg/25 µl 1 h after treatment, respectively). These values were not significantly different from the control strain. In a long-term experiment, Buserelin was administered every 12 h, and LH release was assayed 1 h later. In female G₁₁ KO mice and control strain, serum LH levels reached approximately 500 pg/25 µl within the first hour, then subsided to a steady level (100 pg/25 µl) for 109 h. In male G₁₁ KO mice and in control strain, elevated LH release lasted for 13 h; however, LH levels in the G₁₁ KO male mice did not reach control levels for approximately 49 h. In a similar experimental protocol, the G_q KO male mice released less LH (531 ± 95 pg/25 µl) after 13 h from the start of treatment than the heterozygous male mice (865 ± 57 pg/25 µl), but the female KO mice released more LH (634 ± 56 pg/25 µl) after 1 h from the start of treatment than the heterozygous female mice (346 ± 63 pg/25 µl). However, after the initial LH flare, the LH levels in the heterozygous mice never reached the basal levels achieved by the KO mice. G₁₁ KO mice were less sensitive to low doses (5 ng/per animal) of Buserelin than the respective control mice. Male G₁₁ KO mice produced more testosterone than the control mice after 1 h of stimulation by 2 µg of Buserelin, whereas there was no significant difference in Buserelin stimulated testosterone levels between G_q KO and heterozygous control mice. There was no significant difference in Buserelin stimulated estradiol production in the female G_q KO mice compared with control groups of mice. However, female G₁₁ KO mice produced less estradiol in response to Buserelin (2 µg) compared with control strain. Although there were differences in the dynamics of LH release and steroid production in response to Buserelin treatment compared with control groups of mice, the lack of complete abolition of these processes, such as stimulated LH release, and steroid production, suggests that these G proteins are either not absolutely required or are able to functionally compensate for each other.

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