Scaffolding by A-Kinase Anchoring Protein Enhances Functional Coupling between Adenylyl Cyclase and TRPV1 Channel

• Published in: The Journal of biological chemistry 2013-02, Vol.288 (6), p.3929-3937
• Main Authors: Efendiev, Riad, Bavencoffe, Alexis, Hu, Hongzhen, Zhu, Michael X., Dessauer, Carmen W.
• Format: Article
• Language: English
• Subjects: A Kinase Anchor Proteins - genetics; A Kinase Anchor Proteins - metabolism; Adenylate Cyclase (Adenylyl Cyclase); Adenylyl Cyclases - genetics; Adenylyl Cyclases - metabolism; Adrenergic beta-Agonists - pharmacology; Akap; AKAP79; Animals; Capsaicin - pharmacology; Colforsin - pharmacology; Cyclic AMP (cAMP); Cyclic AMP - genetics; Cyclic AMP - metabolism; Cyclic AMP-Dependent Protein Kinases - genetics; Cyclic AMP-Dependent Protein Kinases - metabolism; Dinoprostone - genetics; Dinoprostone - metabolism; Dorsal Root Ganglia; Ganglia, Spinal - metabolism; Ganglia, Spinal - pathology; HEK293 Cells; Humans; Hyperalgesia - genetics; Hyperalgesia - metabolism; Hyperalgesia - pathology; Mice; Multiprotein Complexes - genetics; Multiprotein Complexes - metabolism; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Prostaglandin E2; Protein Kinase A (PKA); Protein Kinase C - genetics; Protein Kinase C - metabolism; Sensory System Agents - pharmacology; Signal Transduction; TRP Channels; TRPV Cation Channels - genetics; TRPV Cation Channels - metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M112.428144

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 E2. 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. Background: AKAP79 scaffolds TRPV1 channel and PKA to block channel desensitization. Results: Adenylyl cyclase (AC) anchoring to TRPV1-AKAP79-PKA complex sensitizes the channel to forskolin and is required for PGE2 sensitization of TRPV1 in dorsal root ganglia (DRG). Conclusion: AC scaffolding enhances functional coupling between Gs-coupled agonist and effector. Significance: AKAP complexes containing AC and PKA facilitate responses to inflammatory mediators.