title: Different cAMP sources are critically involved in G protein-coupled receptor CRHR1 signaling.
abstract: Corticotropin-releasing hormone receptor 1 (CRHR1) activates G protein-dependent and internalization-dependent signaling mechanisms. Here, we report that the cyclic AMP (cAMP) response of CRHR1 in physiologically relevant scenarios engages separate cAMP sources, involving the atypical soluble adenylyl cyclase (sAC) in addition to transmembrane adenylyl cyclases (tmACs). cAMP produced by tmACs and sAC is required for the acute phase of extracellular signal regulated kinase 1/2 activation triggered by CRH-stimulated CRHR1, but only sAC activity is essential for the sustained internalization-dependent phase. Thus, different cAMP sources are involved in different signaling mechanisms. Examination of the cAMP response revealed that CRH-activated CRHR1 generates cAMP after endocytosis. Characterizing CRHR1 signaling uncovered a specific link between CRH-activated CRHR1, sAC, and endosome-based signaling. We provide evidence of sAC being involved in an endocytosis-dependent cAMP response, strengthening the emerging model of GPCR signaling in which the cAMP response does not occur exclusively at the plasma membrane and introducing the notion of sAC as an alternative source of cAMP.
authors.affiliation: Instituto de Investigación en Biomedicina de Buenos Aires-CONICET-Partner Institute of the Max Planck Society, C1425FQD Buenos Aires, Argentina Departamento de Fisiología, Biología Molecular y Celular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, C1428EHA Buenos Aires, Argentina.
authors.forename: Carolina
authors.identifier: 0000-0001-8881-8453
authors.initials: C
authors.lastname: Inda
authors.affiliation: Instituto de Investigación en Biomedicina de Buenos Aires-CONICET-Partner Institute of the Max Planck Society, C1425FQD Buenos Aires, Argentina Departamento de Fisiología, Biología Molecular y Celular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, C1428EHA Buenos Aires, Argentina.
authors.forename: Paula A
authors.initials: PA
authors.lastname: Dos Santos Claro
authors.affiliation: Instituto de Investigación en Biomedicina de Buenos Aires-CONICET-Partner Institute of the Max Planck Society, C1425FQD Buenos Aires, Argentina Departamento de Fisiología, Biología Molecular y Celular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, C1428EHA Buenos Aires, Argentina.
authors.forename: Juan J
authors.identifier: 0000-0001-7767-0799
authors.initials: JJ
authors.lastname: Bonfiglio
authors.affiliation: Instituto de Investigación en Biomedicina de Buenos Aires-CONICET-Partner Institute of the Max Planck Society, C1425FQD Buenos Aires, Argentina.
authors.forename: Sergio A
authors.initials: SA
authors.lastname: Senin
authors.affiliation: Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, 80804 Munich, Germany.
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Maccarrone
authors.affiliation: Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, 80804 Munich, Germany.
authors.forename: Christoph W
authors.initials: CW
authors.lastname: Turck
authors.affiliation: Instituto de Investigación en Biomedicina de Buenos Aires-CONICET-Partner Institute of the Max Planck Society, C1425FQD Buenos Aires, Argentina Departamento de Fisiología, Biología Molecular y Celular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, C1428EHA Buenos Aires, Argentina ssilberstein@ibioba-mpsp-conicet.gov.ar.
authors.forename: Susana
authors.identifier: 0000-0002-1042-9447
authors.initials: S
authors.lastname: Silberstein
mesh_terms: D041721:3T3-L1 Cells; D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D001639:Bicarbonates / Q000494:pharmacology; D002118:Calcium / Q000494:pharmacology; D002462:Cell Membrane / Q000187:drug effects / Q000201:enzymology; D052680:Corticotrophs / Q000187:drug effects / Q000378:metabolism; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004705:Endocytosis / Q000187:drug effects; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism; D006801:Humans; D051379:Mice; D051381:Rats; D018019:Receptors, Corticotropin-Releasing Hormone / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D012995:Solubility; D000099052:CRF Receptor, Type 1
chemical_list: D001639:Bicarbonates; D020662:Guanine Nucleotide Exchange Factors; D018019:Receptors, Corticotropin-Releasing Hormone; D000099052:CRF Receptor, Type 1; D003346:Corticotropin-Releasing Hormone; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D000262:Adenylyl Cyclases; D002118:Calcium