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Submitted on June 2, 2003
Accepted on August 5, 2003
1 Department of Pharmacology, The University of Iowa, Iowa City, IA 52242
* To whom correspondence should be addressed. E-mail: mario-ascoli{at}uiowa.edu.
The pathways involved in the activation of the ERK1/2 cascade in Leydig cells were examined in MA-10 cells expressing the recombinant hLHR and in primary cultures of rat Leydig cell precursors.
In MA-10 cells expressing the recombinant hLHR, the hCG-induced activation of ERK1/2 is effectively inhibited by overexpression of a cAMP-phosphodiesterase (a manipulation that blunts the hCG-induced cAMP response), by addition of H89 (a selective inhibitor of protein-kinase A) or by overexpression of the heat stable protein kinase A (PKA) inhibitor but not by overexpression of an inactive mutant of this inhibitor. Stimulation of the hLHR did not activate Rap1 but activated Ras in an H89-sensitive fashion. Addition of H89 to MA-10 cells that had been co-transfected with a GTPase-deficient mutant of Ras almost completely inhibited the hLHR-mediated activation of ERK1/2. We also show that 8Br-cAMP activates Ras and ERK1/2 in MA-10 cells and in primary cultures of rat Leydig cells precursors in an H89-sensitive fashion whereas a cAMP analog (8CPT-2Me-cAMP) that is selective for cAMP-dependent guanine nucleotide exchange factor has no effect.
Collectively, our results show that the hLHR-induced phosphorylation of ERK1/2 in Leydig cells is mediated by a protein kinase A-dependent activation of Ras.
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