β-Blocker drugs mediate calcium signaling in native central nervous system neurons by β-arrestin-biased agonism

G protein-coupled receptors (GPCRs), the largest family of signaling receptors expressed in the CNS, mediate the neuropsychiatric effects of a diverse range of clinically relevant drugs. It is increasingly clear that GPCRs can activate distinct G protein-dependent and -independent transduction pathway(s), and that certain drugs differ in the ability to regulate distinct signaling mechanisms linked to the same receptors. A fundamental question in neuropharmacology is whether such biased agonism occurs in physiologically relevant neurons and with endogenous receptors. Here we show that propranolol and carvedilol, two beta-blocker drugs that inhibit beta-adrenergic signaling via heterotrimeric G proteins, function in hippocampal pyramidal neurons as potent and selective activators of an alternate receptor-linked calcium signaling pathway mediated by beta-arrestin-2 and ERK1/2. Our results support the emerging view of beta-arrestin-biased agonism as a significant mechanism of drug action and do so in CNS-derived neurons expressing only native receptors.