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Adrenergic Beta Receptors and Family B Neuropeptide GPCRs and their Signaling Linkage to ERK through NCS-Rapgef2

Friday, September 14, 2018 — Poster Session V

12:00 p.m. – 1:30 p.m.
FAES Terrace
NIMH
NEURO-30

Authors

  • AN Wilson
  • AC Emery
  • W Xu
  • SZ Jiang
  • LE Eiden

Abstract

The 15-member secretin family of G-protein coupled receptors (GPCRs) have in common peptide liganding and coupling through Gs, to cause elevation of intracellular cyclic AMP (cAMP). Recently, a novel cAMP sensor/effector, NCS-Rapgef2, has been characterized that i) links cAMP elevation to activation of the MAP kinase ERK; and ii) is expressed in a neuroendocrine-specific manner in adult mammals (Emery et al., Sci. Signal. 2013). We have surveyed several family B receptors for activation of NCS-Rapgef2, protein kinase A (PKA), and Epac2, the three cAMP sensor/effectors present in the neuroendocrine cell line NS-1. The PAC1, VPAC1, VPAC2 and GLP-1 receptors all cause activation of all three cAMP sensor/effectors, and each leads to a distinct downstream cellular action (these are neuritogenesis, neuron-specific gene expression/survival, and growth arrest, for NCS-Rapgef2, PKA and Epac, respectively). More rapidly-desensitizing Gs-coupled receptors in the rhodopsin family, such as the adrenergic beta receptor type 2 (ADBR2) activate both Epac- and PKA-dependent cAMP signaling, but not NCS-Rapgef2-dependent signaling, presumably due to the requirement for sustained ERK activation for expression of the latter. We postulate that family B neuropeptide signaling in brain and peripheral endocrine tissues mediated through ERK requires activation of NCS-Rapgef2, and that this signaling pathway, and therefore its downstream cellular effects, may be pharmacologically distinguished from those of other cAMP effectors, including PKA and Epac, activated by family B neuropeptide ligands. Additionally, the beta 1, 2, and 3 adrenoreceptors are being studied to determine their dependence on NCS-Rapgef2 and how this controls cellular signaling downstream.

Category: Neuroscience