cAMP-Dependent Protein Kinase Regulates Desensitization of the Capsaicin Receptor (VR1) by Direct Phosphorylation

Bhave, Gautam; Zhu, Weiguo; Wang, Haibin; Brasier, Daniel J.; Oxford, Gerry S.; Gereau, Robert W.

doi:10.1016/s0896-6273(02)00802-4

Cited by 517 publications

(483 citation statements)

References 26 publications

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“…It has been demonstrated that cAMPdependent PKA activation can enhance capsaicin-induced inward current and Ca 2ϩ transient in dorsal root ganglion neurons (36) as well as in vagal sensory neurons (12,22). Indeed, recent studies have successfully delineated several candidate PKA-phosphorylation sites in TRPV1, through which PKA may mediate the sensitization of this channel as well as prevent its desensitization (2).…”

Section: Discussionmentioning

confidence: 99%

Epinephrine enhances the sensitivity of rat vagal chemosensitive neurons: role of β₃-adrenoceptor

Lin

Lee

2007

Journal of Applied Physiology

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Gu Q, Lin Y-S, Lee L-Y. Epinephrine enhances the sensitivity of rat vagal chemosensitive neurons: role of ␤3-adrenoceptor. J Appl Physiol 102: [1545][1546][1547][1548][1549][1550][1551][1552][1553][1554][1555] 2007. First published December 14, 2006; doi:10.1152/japplphysiol.01010.2006.-This study was carried out to determine whether epinephrine alters the sensitivity of rat vagal sensory neurons. In anesthetized rats, inhalation of epinephrine aerosol (1 and 5 mg/ml, 3 min) induced an elevated baseline activity of pulmonary C fibers and enhanced their responses to lung inflation (20 cmH 2O, 10 s) and right atrial injection of capsaicin (0.5 g/kg). In isolated rat nodose and jugular ganglion neurons, perfusion of epinephrine (3 M, 5 min) alone did not produce any detectable change of the intracellular Ca 2ϩ concentration. However, immediately after the pretreatment with epinephrine, the Ca 2ϩ transients evoked by chemical stimulants (capsaicin, KCl, and ATP) were markedly potentiated; for example, capsaicin (50 nM, 15 s)-evoked Ca 2ϩ transient was increased by 106% after epinephrine (P Ͻ 0.05; n ϭ 11). The effect of epinephrine was mimicked by either BRL 37344 (5 M, 5 min) or ICI 215,001 (5 M, 5 min), two selective ␤ 3-adrenoceptor agonists, and blocked by SR 59230A (5 M, 10 min), a selective ␤ 3-adrenoceptor antagonist, whereas pretreatment with phenylephrine (␣ 1-adenoceptor agonist), guanabenz (␣2-adrenoceptor agonist), dobutamine (␤ 1-adrenoceptor agonist), or salbutamol (␤2-adrenoceptor agonist) had no significant effect on capsaicin-evoked Ca 2ϩ transient. Furthermore, pretreatment with SQ 22536 (100 -300 M, 15 min), an adenylate cyclase inhibitor, and H89 (3 M, 15 min), a PKA inhibitor, completely abolished the potentiating effect of epinephrine. Our results suggest that epinephrine enhances the excitability of rat vagal chemosensitive neurons. This sensitizing effect of epinephrine is likely mediated through the activation of ␤ 3-adrenoceptor and intracellular cAMP-PKA signaling cascade. stress; vagal afferents; fura-2; adenylate cyclase; cAMP-dependent protein kinase EPINEPHRINE IS THE PRIMARY CATECHOLAMINE secreted by the adrenal medulla in response to various physiological stresses (41). The physiological functions of epinephrine are mediated through the activation of cell membrane ␣-and ␤-adrenoceptors, both of which belong to the superfamily of seven-transmembrane G-protein-coupled receptors (13). Vagus nerves provide the primary afferent innervation of a broad spectrum of visceral organs and play an important role in the initiation of visceral/viscerosomatic reflexes and the regulation of vegetative functions (24,29). Numerous studies have identified the presence of ␤-adrenoceptors on the vagus nerve in both rats and humans (23,28). Although a sensitizing effect of epinephrine on nociceptors was recently reported (21), whether epinephrine can modulate the excitability of vagal sensory neurons is largely unknown.The aims of the present study were 1) to determine whether epinephrine alters the excit...

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Section: Discussionmentioning

confidence: 99%

Epinephrine enhances the sensitivity of rat vagal chemosensitive neurons: role of β₃-adrenoceptor

Lin

Lee

2007

Journal of Applied Physiology

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“…Furthermore, PKC-mediated phosphorylation also decreases the heat threshold of channel activation (5,6). Similarly, phosphorylation of the N terminus with PKA affects TRPV1 channel function by modulating the rate and extent of receptor desensitization (9). In addition, the C-and N termini display the presence of putative lipid-protein and protein-protein interacting domains that may also contribute to the regulation of receptor channel properties.…”

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confidence: 99%

Regulated Exocytosis Contributes to Protein Kinase C Potentiation of Vanilloid Receptor Activity

Morenilla‐Palao

Planells-Cases

García-Sanz

et al. 2004

Journal of Biological Chemistry

386

302

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The vanilloid receptor-1 (TRPV1) plays a key role in the perception of peripheral thermal and inflammatory pain. TRPV1 expression and channel activity are notably up-regulated by proalgesic agents. The transduction pathways involved in TRPV1 sensitization are still elusive. We have used a yeast two-hybrid screen to identify proteins that associate with the N terminus of TRPV1. We report that two vesicular proteins, Snapin and synaptotagmin IX (Syt IX), strongly interact in vitro and in vivo with the TRPV1 N-terminal domain. In primary dorsal root ganglion neurons, TRPV1 co-distributes in vesicles with Syt IX and the vesicular protein synaptobrevin. Neither Snapin nor Syt IX affected channel function, but they notably inhibited protein kinase C (PKC)-induced potentiation of TRPV1 channel activity with a potency that rivaled the blockade evoked by botulinum neurotoxin A, a potent blocker of neuronal exocytosis. Noteworthily, we found that PKC activation induced a rapid delivery of functional TRPV1 channels to the plasma membrane. Botulinum neurotoxin A blocked the TRPV1 membrane translocation induced by PKC that was activated with a phorbol ester or the metabotropic glutamate receptor mGluR5. Therefore, our results indicate that PKC signaling promotes at least in part the SNARE-dependent exocytosis of TRPV1 to the cell surface. Taken together, these findings imply that activitydependent delivery of channels to the neuronal surface may contribute to the buildup and maintenance of thermal inflammatory hyperalgesia in peripheral nociceptor terminals.TRPV1 1 is a capsaicin-, proton-and heat-sensitive, cationselective ion channel expressed in nociceptors that participates in the transduction of noxious chemical and thermal stimuli by sensory nerve endings in peripheral tissues (1-3). Heterologous expression of TRPV1 cDNA results in ionic currents that recapitulate most of the functional properties displayed by native capsaicin-and heat-activated currents in sensory neurons (1, 2). For instance, TRPV1 exhibits a time-and Ca 2ϩ -dependent desensitization, a long lasting refractory state during which the receptor does not respond to vanilloids or other stimuli (2). In addition, the channel activity of TRPV1 is remarkably upregulated by inflammatory mediators through the activation of phospholipase C and protein kinases A and C (PKA and PKC) signaling pathways (4 -13). Recent evidence shows that an increase in TRPV1 expression in peripheral nociceptors is critical for the maintenance of inflammatory hyperalgesia (14, 15). The involvement of TRPV1 in heat hypersensitivity is further underscored by the reduced sensitivity of mice lacking TRPV1 (16, 17) and by mice treated with receptor-specific antagonists (18).TRPV1 belongs to the family of transient receptor potential channels, which structurally resembles the family of voltagegated potassium or cyclic nucleotide-gated channels (19). Accordingly, these channels are presumed to be tetrameric assemblies of identical subunits (Fig. 1A), although heteromeric assemblies have be...

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“…The desensitization of capsaicin-evoked currents is dependent on external Ca 2ϩ and presumably upon the activity of a Ca 2ϩ -dependent phosphatase (16,17). Recently, Bhave et al (20) suggested that protein kinase A (PKA) controls tachyphylaxis, the reduced response to repeated stimuli. However, the molecular mechanism of VR1 desensitization has remained elusive.…”

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Phosphorylation of Vanilloid Receptor 1 by Ca2+/Calmodulin-dependent Kinase II Regulates Its Vanilloid Binding

Jung

Shin

Lee

et al. 2004

Journal of Biological Chemistry

242

229

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Vanilloid receptor 1 (VR1), a capsaicin receptor, is known to play a major role in mediating inflammatory thermal nociception. Although the physiological role and biophysical properties of VR1 are known, the mechanism of its activation by ligands is poorly understood. Here we show that VR1 must be phosphorylated by Ca 2؉ -calmodulin dependent kinase II (CaMKII) before its activation by capsaicin. In contrast, the dephosphorylation of VR1 by calcineurin leads to a desensitization of the receptor. Moreover, point mutations in VR1 at two putative consensus sites for CaMKII failed to elicit capsaicin-sensitive currents and caused a concomitant reduction in VR1 phosphorylation in vivo. Such mutants also lost their high affinity binding with [ 3 H]resiniferatoxin, a potent capsaicin receptor agonist. We conclude that the dynamic balance between the phosphorylation and dephosphorylation of the VR1 channel by CaMKII and calcineurin, respectively, controls the activation/ desensitization states by regulating VR1 binding. Furthermore, because sensitization by protein kinase A and C converge at these sites, phosphorylation stress in the cell appears to control a wide range of excitabilities in response to various adverse stimuli.

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cAMP-Dependent Protein Kinase Regulates Desensitization of the Capsaicin Receptor (VR1) by Direct Phosphorylation

Cited by 517 publications

References 26 publications

Epinephrine enhances the sensitivity of rat vagal chemosensitive neurons: role of β₃-adrenoceptor

Epinephrine enhances the sensitivity of rat vagal chemosensitive neurons: role of β₃-adrenoceptor

Regulated Exocytosis Contributes to Protein Kinase C Potentiation of Vanilloid Receptor Activity

Phosphorylation of Vanilloid Receptor 1 by Ca2+/Calmodulin-dependent Kinase II Regulates Its Vanilloid Binding

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cAMP-Dependent Protein Kinase Regulates Desensitization of the Capsaicin Receptor (VR1) by Direct Phosphorylation

Cited by 517 publications

References 26 publications

Epinephrine enhances the sensitivity of rat vagal chemosensitive neurons: role of β3-adrenoceptor

Epinephrine enhances the sensitivity of rat vagal chemosensitive neurons: role of β3-adrenoceptor

Regulated Exocytosis Contributes to Protein Kinase C Potentiation of Vanilloid Receptor Activity

Phosphorylation of Vanilloid Receptor 1 by Ca2+/Calmodulin-dependent Kinase II Regulates Its Vanilloid Binding

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Epinephrine enhances the sensitivity of rat vagal chemosensitive neurons: role of β₃-adrenoceptor

Epinephrine enhances the sensitivity of rat vagal chemosensitive neurons: role of β₃-adrenoceptor