title: Cross-talk from β-adrenergic receptors modulates α2A-adrenergic receptor endocytosis in sympathetic neurons via protein kinase A and spinophilin.
abstract: Inter-regulation of adrenergic receptors (ARs) via cross-talk is a long appreciated but mechanistically unclear physiological phenomenon. Evidence from the AR literature and our own extensive studies on regulation of α2AARs by the scaffolding protein spinophilin have illuminated a potential novel mechanism for cross-talk from β to α2ARs. In the present study, we have characterized a mode of endogenous AR cross-talk in native adrenergic neurons whereby canonical βAR-mediated signaling modulates spinophilin-regulated α2AAR endocytosis through PKA. Our findings demonstrate that co-activation of β and α2AARs, either by application of endogenous agonist or by simultaneous stimulation with distinct selective agonists, results in acceleration of endogenous α2AAR endocytosis in native neurons. We show that receptor-independent PKA activation by forskolin is sufficient to accelerate α2AAR endocytosis and that α2AAR stimulation alone drives accelerated endocytosis in spinophilin-null neurons. Endocytic response acceleration by β/α2AAR co-activation is blocked by PKA inhibition and lost in spinophilin-null neurons, consistent with our previous finding that spinophilin is a substrate for phosphorylation by PKA that disrupts its interaction with α2AARs. Importantly, we show that α2AR agonist-mediated α2AAR/spinophilin interaction is blocked by βAR co-activation in a PKA-dependent fashion. We therefore propose a novel mechanism for cross-talk from β to α2ARs, whereby canonical βAR-mediated signaling coupled to PKA activation results in phosphorylation of spinophilin, disrupting its interaction with α2AARs and accelerating α2AAR endocytic responses. This mechanism of cross-talk has significant implications for endogenous adrenergic physiology and for therapeutic targeting of β and α2AARs.
authors: From the Departments of Cell, Developmental, & Integrative Biology and.
authors: Christopher
authors: C
authors: Cottingham
authors: Roujian
authors: R
authors: Lu
authors: Kai
authors: K
authors: Jiao
authors: Qin
authors: Q
authors: Wang
mesh_terms: D058647:Adrenergic alpha-2 Receptor Agonists / Q000494:pharmacology; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D019390:Arrestins / Q000378:metabolism; D005576:Colforsin / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D004622:Embryo, Mammalian / Q000166:cytology; D004705:Endocytosis / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D004837:Epinephrine / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D007545:Isoproterenol / Q000494:pharmacology; D051379:Mice; D008840:Microfilament Proteins / Q000172:deficiency / Q000378:metabolism*; D008954:Models, Biological; D050505:Mutant Proteins / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000378:metabolism*; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism*; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013564:Sympathetic Nervous System / Q000166:cytology; D000099273:Neurabins
chemical_list: D058647:Adrenergic alpha-2 Receptor Agonists; D000318:Adrenergic beta-Agonists; D019390:Arrestins; D005576:Colforsin; D017868:Cyclic AMP-Dependent Protein Kinases; D004837:Epinephrine; D007545:Isoproterenol; D008840:Microfilament Proteins; D050505:Mutant Proteins; D009419:Nerve Tissue Proteins; D018341:Receptors, Adrenergic, alpha-2; D011943:Receptors, Adrenergic, beta; D000099273:Neurabins; C082333:arrestin3
keywords: Adrenergic Receptor; Cross-talk; Endocytosis; G Protein-coupled receptors (GPCR); Neurons; Protein Kinase A (PKA); Spinophilin
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