Different cAMP sources are critically involved in G protein-coupled receptor CRHR1 signaling.

J Cell Biol

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

Published: July 2016

AI Article Synopsis

  • Corticotropin-releasing hormone receptor 1 (CRHR1) activates different signaling pathways, relying on both transmembrane adenylyl cyclases and a unique soluble adenylyl cyclase (sAC) for producing cyclic AMP (cAMP).
  • While both types of adenylyl cyclases are necessary for the initial activation of extracellular signal regulated kinase 1/2, only sAC is crucial for the sustained signaling that follows CRH stimulation and receptor internalization.
  • The study highlights that CRH-activated CRHR1 can generate cAMP after being internalized, suggesting that cAMP signaling can occur within the cell rather than just at the surface, with sAC serving

Article 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.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4949449PMC
http://dx.doi.org/10.1083/jcb.201512075DOI Listing

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