ATP binding site on the C-terminus of the vanilloid receptor

Grycová, Lenka; Lánský, Zdeněk; Friedlova, Eliska; Vlachová, Viktorie; Kubala, Martin; Obšilová, Veronika; Obšil, Tomáš; Teisinger, Jan

doi:10.1016/j.abb.2007.06.035

Cited by 16 publications

(15 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…By contrast, the pH sensor in TRPV1 is extracellular [Tousova et al, 2005]. The N-terminus ankyrin repeats of TRPV1 contain a multiligand domain [Lishko et al, 2007] whereas the ATP binding site was localized to the C-terminus of TRPV1 [Grycova et al, 2007]. Given this complex structure of ligand activation, it is hardly surprising that TRPV1 antagonists show selectivity in their pharmacological profile.…”

Section: Molecular Pharmacology Of Trpv1: Implications For Analgesia mentioning

confidence: 92%

Medicinal chemistry of the vanilloid (Capsaicin) TRPV1 receptor: current knowledge and future perspectives

Gharat

Szállaśi

2007

Drug Development Research

View full text Add to dashboard Cite

In peripheral sensory neurons, the vanilloid receptor TRPV1 (transient receptor potential vanilloid subfamily, member 1) functions as a molecular integrator of painful stimuli, including those mediated by capsaicin, acid, and heat. Antagonist blockade of TRPV1 activation is under investigation by several pharmaceutical companies in an effort to identify novel agents for pain management. TRPV1 is also expressed, albeit at lower levels, in the brain and in non-neuronal tissues, where its function(s) remains elusive. The contribution of TRPV1 receptor activity to physiological reflexes and disease states is complex and is only beginning to be understood. Consequently, the resultant effects of TRPV1 antagonists on the body may be unforeseen. Indeed, clinical trials with a number of TRPV1 antagonists were recently terminated due to their marked hyperthermic activity. In this review article, the medicinal chemistry of TRPV1 antagonists is discussed inasmuch as it relates to the efficacy, safety, tolerability and potential side effects of these compounds. In addition, the available information on the current status of the clinical trials with TRPV1 antagonists is summarized. Drug Dev Res 68: 477-497, 2007.

show abstract

Section: Molecular Pharmacology Of Trpv1: Implications For Analgesia mentioning

confidence: 92%

Medicinal chemistry of the vanilloid (Capsaicin) TRPV1 receptor: current knowledge and future perspectives

Gharat

Szállaśi

2007

Drug Development Research

View full text Add to dashboard Cite

show abstract

“…Evidence was later presented that TRPV1 desensitization might also involve other Ca 2+ -dependent pathways, in particular Ca 2+ -dependent phospholipase pathways downstream of G-protein coupled or tyrosine kinase receptors [50]. A role for adenosine triphosphate (ATP) has also been implied, based on the early evidence that ATP sensitizes TRPV1, and single point mutations at Asp178 and Lys735 within the two putative Walker type nucleotidebinding domains abolished this effect [51,52]. In recent years, considerable attention has been directed towards determining the possible involvement of phosphatidylinositol 4,5-bisphosphate (PIP 2 ) in TRPV1 activation and desensitization.…”

Section: Modulation Of Trpv1 By Pipmentioning

confidence: 97%

A “Cute” Desensitization of TRPV1

Touška¹,

Marsakova²,

Teisinger³

et al. 2011

CPB

Self Cite

View full text Add to dashboard Cite

Capsaicin and other vanilloids selectively excite and subsequently desensitize pain-conducting nerve fibers (nociceptors) and this process contributes to the analgesic (and thus therapeutically relevant) effects of these compounds. Such a desensitization process is triggered by the activation of the transient receptor potential vanilloid subtype 1 receptor channels (TRPV1) that open their cationic pores, permeable to sodium, potassium and calcium (Ca(2+)) ions. Depending on the duration of capsaicin exposure and the external calcium concentration, the Ca(2+) influx via TRPV1 channels desensitizes the channels themselves, which, from the cellular point of view, represents a feedback mechanism protecting the nociceptive neuron from toxic Ca(2+) overload. The 'acute desensitization' accounts for most of the reduction in responsiveness occurring within the first few (~20) seconds after the vanilloids are administered to the cell for the first time. Another form of desensitization is 'tachyphylaxis', which is a reduction in the response to repeated applications of vanilloid. The wealth of pathways following TRPV1 activation that lead to increased intracellular Ca(2+) levels and both forms of desensitization is huge and they might utilise just about every known type of signalling molecule. This review will not attempt to cover all historical aspects of research into all these processes. Instead, it will try to highlight some new challenging thoughts on the important phenomenon of TRPV1 desensitization and will focus on the putative mechanisms that are thought to account for the acute phase of this process.

show abstract

“…A number of studies have demonstrated that the cytoplasmic regions of TRP channels bind agonists and regulatory molecules such as ATP, calmodulin (CaM) and phosphatidyl inositol-4, 5-bisphosphate (PIP2) [8], [9], [10], [11], [12], [13], [14], [15]. PIP2 is a minor component of the plasma membrane with multiple functions.…”

Section: Introductionmentioning

confidence: 99%

Integrative Binding Sites within Intracellular Termini of TRPV1 Receptor

et al. 2012

Self Cite

View full text Add to dashboard Cite

TRPV1 is a nonselective cation channel that integrates wide range of painful stimuli. It has been shown that its activity could be modulated by intracellular ligands PIP2 or calmodulin (CaM). The detailed localization and description of PIP2 interaction sites remain unclear. Here, we used synthesized peptides and purified fusion proteins of intracellular regions of TRPV1 expressed in E.coli in combination with fluorescence anisotropy and surface plasmon resonance measurements to characterize the PIP2 binding to TRPV1. We characterized one PIP2 binding site in TRPV1 N-terminal region, residues F189-V221, and two independent PIP2 binding sites in C–terminus: residues K688-K718 and L777-S820. Moreover we show that two regions, namely F189-V221 and L777-S820, overlap with previously localized CaM binding sites. For all the interactions the equilibrium dissociation constants were estimated. As the structural data regarding C-terminus of TRPV1 are lacking, restraint-based molecular modeling combined with ligand docking was performed providing us with structural insight to the TRPV1/PIP2 binding. Our experimental results are in excellent agreement with our in silico predictions.

show abstract

ATP binding site on the C-terminus of the vanilloid receptor

Cited by 16 publications

References 52 publications

Medicinal chemistry of the vanilloid (Capsaicin) TRPV1 receptor: current knowledge and future perspectives

Medicinal chemistry of the vanilloid (Capsaicin) TRPV1 receptor: current knowledge and future perspectives

A “Cute” Desensitization of TRPV1

Integrative Binding Sites within Intracellular Termini of TRPV1 Receptor

Contact Info

Product

Resources

About

ATP binding site on the C-terminus of the vanilloid receptor

Cited by 16 publications

References 52 publications

Medicinal chemistry of the vanilloid (Capsaicin) TRPV1 receptor: current knowledge and future perspectives

Medicinal chemistry of the vanilloid (Capsaicin) TRPV1 receptor: current knowledge and future perspectives

A &#x201C;Cute&#x201D; Desensitization of TRPV1

Integrative Binding Sites within Intracellular Termini of TRPV1 Receptor

Contact Info

Product

Resources

About

A “Cute” Desensitization of TRPV1