Examining the Structural Requirements for Beta Receptor Isoform Selectivity of cAMP-dependent Signaling Through NCS/Rapgef2

Authors

• CD Westover
• KB Kluska
• AC Emery
• JC Santiago
• W Xu
• MV Eiden
• LE Eiden

Abstract

G Protein-Coupled Receptors (GPCRs) comprise a large protein family of seven transmembrane domain receptors that are linked to a number of diseases. The adrenergic receptors ADRB1 (β1) and ADRB2 (β2) are GPCRs that mediate the actions of norepinephrine (NE) and epinephrine (E) within the sympathetic nervous system and the brain. The NE-preferring ADRB1 is located in the heart, while the E-preferring ADRB2 is located on non-cardiac (smooth) muscle in the lung, gut, vasculature and elsewhere. The two receptor subtypes are expressed equally in brain, where their distinct functions are less obvious than in the periphery. Clues to differential signaling in the brain may be obtained from an expanded knowledge of how these two receptors signal in neurons. It has been reported that while both ADRB1 and ADRB2 cause cAMP elevation, only ADRB2 activates signaling via arrestin, which leads in turn to activation of the MAP kinase Extracellular Signal-regulated Kinase (ERK). Recently, we have shown that a second pathway for activation of ERK by Gs-coupled GPCRs exists: the family B receptor PAC1 causes ERK activation and ERK-dependent neuritogenesis in neuroendocrine cells (see Emery, et al., 2013, Science Signaling 6:ra5). We are now in the process of determining i) the ERK signaling repertoire and pathways for ADRB1 and ADRB2 in neuronal cells, ii) the structural basis for differences in ADRB1 and ADRB2 signaling in neurons, and iii) differences in the cellular dynamics of ERK activation that might explain differential post-synaptic actions of ADRB1 and ADRB2 in the CNS.

Scientific Focus Area: Molecular Pharmacology

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