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Here, we report neuronal excitability of \u03b2-blockers carvedilol and alprenolol at clinically relevant nanomolar concentrations. Carvedilol and alprenolol activate \u03b22AR, which promote G protein signaling and cAMP\/PKA activities without action of G protein receptor kinases (GRKs). The cAMP\/PKA activities are restricted within the immediate vicinity of activated \u03b22AR, leading to selectively enhance PKA-dependent phosphorylation and stimulation of endogenous L-type calcium channel (LTCC) but not AMPA receptor in rat hippocampal neurons. Moreover, we have engineered a mutant \u03b22AR that lacks the catecholamine binding pocket. This mutant is preferentially activated by carvedilol but not the orthosteric agonist isoproterenol. Carvedilol activates the mutant \u03b22AR in mouse hippocampal neurons augmenting LTCC activity through cAMP\/PKA signaling. Together, our study identifies a mechanism by which \u03b2-blocker-dependent activation of GPCRs promotes spatially restricted cAMP\/PKA signaling to selectively target membrane downstream effectors such as LTCC in neurons.<\/jats:p>","DOI":"10.7554\/elife.49464","type":"journal-article","created":{"date-parts":[[2019,10,14]],"date-time":"2019-10-14T08:02:00Z","timestamp":1571040120000},"source":"Crossref","is-referenced-by-count":16,"title":["\u03b2-blockers augment L-type Ca2+ channel activity by targeting spatially restricted \u03b22AR signaling in neurons"],"prefix":"10.7554","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1559-3895","authenticated-orcid":true,"given":"Ao","family":"Shen","sequence":"first","affiliation":[{"name":"Key Laboratory of Molecular Target and Clinical Pharmacology, State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences & the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 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