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

Jung, James A.; Shin, Jae Soo; Lee, Soon Youl; Hwang, Sun Wook; Koo, Jae-Yeon; Cho, Hawon; Oh, Uhtaek

doi:10.1074/jbc.m311448200

Cited by 244 publications

(234 citation statements)

References 48 publications

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“…It has been reported recently that the phosphorylation of VR1 is required for its ligand binding (35). Increased phosphorylation of VR1 in DRGs from diabetic rats suggests that the number of channels available for ligand binding is enhanced in diabetic rats because only modest phosphorylation of VR1 was observed in DRGs from control rats.…”

Section: Discussionmentioning

confidence: 93%

“…4). After the VR1 channel has been opened by capsaicin, an increase in intracellular Ca 2ϩ could activate the phosphatase calcineurin, which leads to dephosphorylation of VR1 and therefore desensitization (35). With repeated stimuli, the impairment of VR1 desensitization would keep channels open and allow continued cation influx into the cell, contributing to persistent hyperactivity.…”

Section: Discussionmentioning

confidence: 99%

“…Impaired Capsaicin-induced Desensitization of VR1 Receptor in DRG Neurons-Extracellular Ca 2ϩ -dependent desensitization of VR1 has been observed in patch clamp experiments when using both heterologous expression systems and native DRG neurons (35). The inactivation of nociceptive neurons by capsaicin has generated extensive research on the possible therapeutic effectiveness of capsaicin as a clinical analgesic tool (12,13).…”

Section: Diabetic Neuropathy Is Associated With Increasedmentioning

confidence: 99%

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Early Painful Diabetic Neuropathy Is Associated with Differential Changes in the Expression and Function of Vanilloid Receptor 1

Hong

Wiley

2005

Journal of Biological Chemistry

211

136

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Diabetes mellitus is associated with one or more kinds of stimulus-evoked pain including hyperalgesia and allodynia. The mechanisms underlying painful diabetic neuropathy remain poorly understood. Previous studies demonstrate an important role of vanilloid receptor 1 (VR1) in inflammation and injury-induced pain. Here we investigated the function and expression of VR1 in dorsal root ganglion (DRG) neurons isolated from streptozotocin-induced diabetic rats between 4 and 8 weeks after onset of diabetes. DRG neurons from diabetic rats showed significant increases in capsaicin-and protonactivated inward currents. These evoked currents were completely blocked by the capsaicin antagonist capsazepine. Capsaicin-induced desensitization of VR1 was down-regulated, whereas VR1 re-sensitization was upregulated in DRG neurons from diabetic rats. The protein kinase C (PKC) activator phorbol 12-myristate 13-acetate blunted VR1 desensitization, and this effect was reversible in the presence of the PKC inhibitor bisindolylmaleimide I. Compared with the controls, VR1 protein was decreased in DRG whole-cell homogenates from diabetic rats, but increased levels of VR1 protein were observed on plasma membranes. Of interest, the tetrameric form of VR1 increased significantly in DRGs from diabetic rats. Increased phosphorylation levels of VR1 were also observed in DRG neurons from diabetic rats. Colocalization studies demonstrated that VR1 expression was increased in large myelinated A-fiber DRG neurons, whereas it was decreased in small unmyelinated C-fiber neurons as a result of diabetes. These results suggest that painful diabetic neuropathy is associated with altered cell-specific expression of the VR1 receptor that is coupled to increased function through PKC-mediated phosphorylation, oligomerization, and targeted expression on the cell surface membrane.Painful neuropathy is one of the most common complications in early to intermediate stages of diabetes mellitus. Diabetic patients frequently exhibit one or more kinds of stimulusevoked pain, including increased responsiveness to noxious stimuli (hyperalgesia) as well as a hyper-responsiveness to normally innocuous stimuli (allodynia) that are often concurrent with a paradoxical loss of stimulus-evoked sensation (1, 2). The underlying mechanisms of painful diabetic neuropathy remain elusive. Similar to human painful diabetic neuropathy, animal models such as streptozotocin (STZ) 1 -induced diabetic mice or rats demonstrate early functional and biochemical abnormalities including thermal hyperalgesia and mechanical allodynia (3-6). It has been suggested that hyperactivity of small, unmyelinated C-fibers results in hyperalgesia and allodynia in this model (6, 7). Khan et al. (4) reported that A-fiber afferents in diabetic rats developed abnormal spontaneous discharges and increased sensitivity to mechanical stimuli, suggesting a role of large A-fiber neurons in addition to nociceptive C-fibers in the development of diabetic neuropathic pain.Capsaicin, the pungent ingredient in hot p...

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Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Section: Diabetic Neuropathy Is Associated With Increasedmentioning

confidence: 99%

See 1 more Smart Citation

Early Painful Diabetic Neuropathy Is Associated with Differential Changes in the Expression and Function of Vanilloid Receptor 1

Hong

Wiley

2005

Journal of Biological Chemistry

211

136

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“…The dynamic balance between the phosphorylation and dephosphorylation of TRPV1 channels by CaMKII and calcineurin, respectively, may control the activation/desensitization states by regulating TRPV1 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 (Jung et al 2004). NGF induced rapid sensitization of nociceptive neurons can be blocked by pharmacological interference with CaM KII, while the blockage of PKA was without effect (Bonnington and McNaughton 2003).…”

Section: Ca 2+ -Calmodulin Dependent Kinasementioning

confidence: 99%

Structure-function analysis of TRPV channels

Niemeyer

2005

Naunyn-Schmiedeberg's Arch Pharmacol

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In recent years many new members of the family of TRP ion channels have been identified. These channels are classified into several subgroups and participate in many sensory and physiological functions. TRPV channels are important for the perception of pain, temperature sensing, osmotic regulation, and maintenance of calcium homeostasis, and much recent research concerns the identification of protein domains involved in mediating specific channel functions. Recent literature on TRPV channel subunit composition, protein domains required for subunit assembly, trafficking, and regulation will be reviewed and discussed.

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“…Desensitization of TRPV1 to capsaicin also involves a number of intracellular components including PKA, ATP and calmodulin [68,[72][73][74][75]]. There appears to be a dynamic balance between phosphorylation and dephosphorylation of the TRPV1 channel that controls the activation/desensitization state of the channel [71,76].…”

Section: Trpv1 As Polymodal Sensor Expressed On Peptidergic Sensory Nmentioning

confidence: 99%

TRPV1 Antagonists as Analgesic Agents

Trevisani

Gatti²

2013

TOPAINJ

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Abstract:The last decade (2001 -2010), declared as the Decade of Pain Control and Research by the United States Congress, brought significantly advances in our understanding of pain biology. Unfortunately, this has not translated into additional effective treatments of chronic pain conditions. Chronic pain is a debilitating and complex clinical state usually associated with diabetic neuropathy, postherpetic neuralgia, low back pathology, fibromyalgia, and neurological disorders. Standard pain drugs, even narcotic opioid analgesic agents, often provide unsatisfactory pain relief while causing important side-effect such as sedation, tolerance, dependence, respiratory depression and constipation. Furthermore, the effective management of chronic pain needs a multidisciplinary management approach and still represents one of the most urgent unmet medical need. Recently, preclinical research has uncovered new molecular mechanisms underlying the generation and transduction of pain, many of which represent new targets for innovative pharmacological interventions. This review focuses on Transient Receptor Potential (TRP) Vanilloid Type 1 (TRPV1) channel as a target for treating chronic pain. TRPV1 is a multifunctional ion channel involved in thermosensation (heat) and taste perception. Importantly, TRPV1 also functions as a molecular integrator for a broad variety of seemingly unrelated noxious stimuli. Indeed, TRPV1 is thought to be a major transducer of the thermal hyperalgesia that follows inflammation and/or tissue injury. Desensitization to topical TRPV1 agonists (e.g. capsaicin creams and patches) has been in clinical use for decades to treat chronic painful conditions like diabetic neuropathy. Most recently, a number of potent, small molecule TRPV1 antagonists have been advanced into clinical trials for pain relief. Perhaps not unexpectedly given the prominent role of TRPV1 in thermosensation, some of these antagonists showed worrisome adverse effects (hyperthermia and impaired noxious heat sensation) in humans, leading to their withdrawal from clinical trials. However, recent reports of TRPV1 antagonists that do not affect core body temperature in preclinical species suggest a potential opportunity to reduce at least this important side effect.

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

Cited by 244 publications

References 48 publications

Early Painful Diabetic Neuropathy Is Associated with Differential Changes in the Expression and Function of Vanilloid Receptor 1

Early Painful Diabetic Neuropathy Is Associated with Differential Changes in the Expression and Function of Vanilloid Receptor 1

Structure-function analysis of TRPV channels

TRPV1 Antagonists as Analgesic Agents

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