A new molecular sensor controlling cAMP activation of ERK

Abstract

The signal transduction pathway linking cAMP elevation through GPCR‐Gs stimulation to ERK activation is incompletely understood. We recently reported that cAMP‐ and ERK‐dependent neuritogenesis in NS‐1 cells initiated by activation of the GPCR PAC1 occurs independently of both PKA and Epac activation, revealing the existence of an additional cAMP sensor (NCS, for neuritogenic cAMP sensor) (Emery and Eiden, FASEB J, 26: 3199, 2012). The adenylate cyclase (AC) inhibitor SQ22,536 blocks cAMP‐dependent ERK activation without affecting either CREB phosphoryation or Epac‐dependent Rap1 GTP loading, thus identifying NCS as a new target of SQ22,356 (see Emery et al., doi:10.1124/mol.112.081760). The pharmacological profile of the NCS has facilitated its molecular identification as a member of the Ras guanine nucleotide exchange factor superfamily. The characteristics of NCS cAMP binding studied in bovine chromaffin cells, and NCS‐dependent ERK signaling studied via gain‐of‐function in HEK293 cells, suggests a previously unremarked and neuroendocrine cell‐specific signaling pathway, GPCR→Gs→AC→cAMP→NCS→Rap1→Braf→MEK, connecting neuropeptide receptor occupancy to ERK activation.Supported by NIMH‐IRP project ZO1‐MH002386.