title: Multistep regulation of Leydig cell function.
abstract: LH controls Leydig cell steroidogenesis by interaction with specific membrane receptors initiating membrane coupling events. Stimulation of the androgen pathways occurs mainly through cAMP mediated mechanism including LH induced guanyl nucleotide binding, membrane phosphorylation and adenylate cyclase activation. cAMP dependent kinase activation presumably causes phosphorylation of key proteins of the steroidogenic pathway and consequent increase in testosterone production. The hormone also appears to facilitate the androgen stimulus by a cyclic AMP independent mechanism located at the plasma membrane or intracellular sites. The stimulatory event can be negatively influenced by the action of certain peptide hormones (i.e. angiotensin II) through the guanyl nucleotide inhibitory subunit of adenylate cyclase (Gi). In recent studies we have presented evidence for a Ca2+ sensitive kinase system present in purified cell membranes. Gpp(NH)p, GTP, and phospholipid in presence of nanomolar Ca2+ induce phosphate incorporation into Mr 44,500 substrate with marked inhibition at microM Ca2+. Similarly a biphasic pattern of activation was observed with adenylate cyclase activity. Membrane phosphorylation may be a modifier of LH-stimulated adenylate cyclase activity and possibly other LH induced actions in the activated Leydig cell membrane. Furthermore we have defined the stimulatory effects of forskolin on all Leydig cell cyclic AMP pools and have provided additional evidence of functional compartmentalization and/or cAMP independent facilitory stimulus of steroidogenesis by the trophic hormone. The demonstration of a novel high affinity inhibitory action of forskolin upon adenylate cyclase activity and cyclic AMP generation mediated by the Gi subunit of adenylate cyclase has provided a new approach for direct evaluation of functional inhibitory influence of Gi subunit in the Leydig cell. The cultured fetal Leydig cell system has provided a useful model to elucidate mechanisms involved in the development of gonadotropin induced estradiol mediated desensitization of steroidogenesis. We have isolated from the fetal testis a small population (2-5% of total) of transitional cells with morphological characteristics of cells found in 15 day postnatal testis but functional capabilities of the adult cell. We have also demonstrated after appropriate treatment (i.e. estrogen, and frequent or a high gonadotropin dose) the emergence of a functional adult-like cell type from the fetal Leydig cell population.
authors.affiliation: Section on Molecular Endocrinology, National Institutes of Child Health and Human Development, Bethesda, MD 20892.
authors.forename: M L
authors.initials: ML
authors.lastname: Dufau
authors.forename: A
authors.initials: A
authors.lastname: Khanum
authors.forename: C A
authors.initials: CA
authors.lastname: Winters
authors.forename: C H
authors.initials: CH
authors.lastname: Tsai-Morris
mesh_terms: D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D006063:Chorionic Gonadotropin / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000502:physiology; D003570:Cytidine Triphosphate / Q000502:physiology; D019204:GTP-Binding Proteins / Q000378:metabolism; D007985:Leydig Cells / Q000187:drug effects / Q000502:physiology*; D007986:Luteinizing Hormone / Q000494:pharmacology; D008297:Male; D051381:Rats; D013256:Steroids / Q000096:biosynthesis; D013737:Testis / Q000196:embryology
chemical_list: D006063:Chorionic Gonadotropin; D013256:Steroids; D005576:Colforsin; D003570:Cytidine Triphosphate; D007986:Luteinizing Hormone; D000242:Cyclic AMP; D019204:GTP-Binding Proteins