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bioRxiv · 10.1101/668913

β-blockers augment L-type Ca2+ channel activity by target-selective spatially restricted β2AR-cAMP-PKA signaling in neurons

Shen, A.·Chen, D.·Kaur, M.·Xu, B.·Shi, Q.·Martinez, J.·Man, K. N. M.·Hell, J. W.·Navedo, M. F.·Yu, X.·Xiang, Y.
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Abstract

G protein-coupled receptors (GPCRs) transduce pleiotropic intracellular signals in mammalian cells. Here, we report that some antagonists of {beta} adrenergic receptors ({beta}ARs) such as {beta}-blocker carvedilol and alprenolol activate {beta}2AR at nanomolar concentrations, which promote G protein signaling and cAMP/PKA activity without action of G protein receptor kinases (GRKs). The cAMP/PKA signal is restricted within the local plasma membrane domain, leading to selectively enhance PKA-dependent augment of endogenous L-type calcium channel (LTCC) activity but not AMPA receptor in hippocampal neurons. Moreover, we have engineered a mutant {beta}2AR that lacks serine 204 and 207 in the catecholamine binding pocket. This mutant can be preferentially activated by carvedilol but not the orthosteric agonist isoproterenol. Carvedilol activates the mutant {beta}2AR in hippocampal neurons augmenting LTCC activity through cAMP/PKA signaling. Together, our study identifies a mechanism by which {beta}-blocker-dependent activation of GPCRs at low ligand concentrations promotes local cAMP/PKA signaling to selectively target membrane downstream effectors such as LTCC in neurons.

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Shen, A., Chen, D., Kaur, M., Xu, B., Shi, Q., Martinez, J., Man, K. N. M., Hell, J. W., Navedo, M. F., Yu, X., Xiang, Y.. 2019-06-13. β-blockers augment L-type Ca2+ channel activity by target-selective spatially restricted β2AR-cAMP-PKA signaling in neurons. https://doi.org/10.1101/668913

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