title: Scaffolding by A-kinase anchoring protein enhances functional coupling between adenylyl cyclase and TRPV1 channel.
abstract: Scaffolding proteins often bring kinases together with their substrates to facilitate cell signaling. This arrangement is critical for the phosphorylation and regulation of the transient receptor potential vanilloid 1 (TRPV1) channel, a key target of inflammatory mediators such as prostaglandins. The protein kinase A anchoring protein AKAP79/150 organizes a multiprotein complex to position protein kinase A (PKA) and protein kinase C (PKC) in the immediate proximity of TRPV1 channels to enhance phosphorylation efficiency. This arrangement suggests that regulators upstream of the kinases must also be present in the signalosome. Here, we show that AKAP79/150 facilitates a complex containing TPRV1 and adenylyl cyclase (AC). The anchoring of AC to this complex generates local pools of cAMP, shifting the concentration of forskolin required to attenuate capsaicin-dependent TRPV1 desensitization by ∼100-fold. Anchoring of AC to the complex also sensitizes the channel to activation by β-adrenergic receptor agonists. Significant AC activity is found associated with TRPV1 in dorsal root ganglia. The dissociation of AC from an AKAP150-TRPV1 complex in dorsal root ganglia neurons abolishes sensitization of TRPV1 induced by forskolin and prostaglandin E(2). Thus, the direct anchoring of both PKA and AC to TRPV1 by AKAP79/150 facilitates the response to inflammatory mediators and may be critical in the pathogenesis of thermal hyperalgesia.
authors.affiliation: Department of Integrative Biology and Pharmacology, University of Texas Health Science Center at Houston, Houston, Texas 77030, USA.
authors.forename: Riad
authors.initials: R
authors.lastname: Efendiev
authors.forename: Alexis
authors.initials: A
authors.lastname: Bavencoffe
authors.forename: Hongzhen
authors.initials: H
authors.lastname: Hu
authors.forename: Michael X
authors.initials: MX
authors.lastname: Zhu
authors.forename: Carmen W
authors.initials: CW
authors.lastname: Dessauer
mesh_terms: D054758:A Kinase Anchor Proteins / Q000235:genetics / Q000378:metabolism*; D000262:Adenylyl Cyclases / Q000235:genetics / Q000378:metabolism*; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D002211:Capsaicin / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000235:genetics / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism; D015232:Dinoprostone / Q000235:genetics / Q000378:metabolism; D005727:Ganglia, Spinal / Q000378:metabolism* / Q000473:pathology; D057809:HEK293 Cells; D006801:Humans; D006930:Hyperalgesia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism; D018689:Sensory System Agents / Q000494:pharmacology; D050916:TRPV Cation Channels / Q000235:genetics / Q000378:metabolism*
chemical_list: D054758:A Kinase Anchor Proteins; C487775:AKAP5 protein, human; D000318:Adrenergic beta-Agonists; C520665:Akap5 protein, mouse; D046912:Multiprotein Complexes; D009419:Nerve Tissue Proteins; D018689:Sensory System Agents; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human; C493921:TRPV1 protein, mouse; D005576:Colforsin; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D000262:Adenylyl Cyclases; D015232:Dinoprostone; D002211:Capsaicin