Functionally Important Amino Acid Residues in the Transient Receptor Potential Vanilloid 1 (TRPV1) Ion Channel - An Overview of the Current Mutational Data

Abstract

This review aims to create an overview of the currently available results of site-directed mutagenesis studies on transient receptor potential vanilloid type 1 (TRPV1) receptor. Systematization of the vast number of data on the functionally important amino acid mutations of TRPV1 may provide a clearer picture of this field, and may promote a better understanding of the relationship between the structure and function of TRPV1. The review summarizes information on 112 unique mutated sites along the TRPV1, exchanged to multiple different residues in many cases. These mutations influence the effect or binding of different agonists, antagonists, and channel blockers, alter the responsiveness to heat, acid, and voltage dependence, affect the channel pore characteristics, and influence the regulation of the receptor function by phosphorylation, glycosylation, calmodulin, PIP2, ATP, and lipid binding. The main goal of this paper is to publish the above mentioned data in a form that facilitates in silico molecular modelling of the receptor by promoting easier establishment of boundary conditions. The better understanding of the structure-function relationship of TRPV1 may promote discovery of new, promising, more effective and safe drugs for treatment of neurogenic inflammation and pain-related diseases and may offer new opportunities for therapeutic interventions.

Understanding TRPV1 activation by ligands: Insights from the binding modes of capsaicin and resiniferatoxin

“…This observation indicates that these interactions are essential for ligand binding and TRPV1 activity. Our results are consistent with the mutation studies of Tyr511, Met547, Thr550, Arg557, and Glu570, which were reported to be important for CAPS and RTX binding (29). We suggest that other residues, whose role has not yet been investigated experimentally, might be crucial for binding to the vanilloid pocket, including Leu515, Leu553, Tyr-554, Ile573, and Phe-587.…”

Structure and Function of the ThermoTRP Channel Pore

“…When individual residues of the TRPV1 S6 were mutated to a cysteine (after removing an endogenous cysteine with the C157A mutation), it allowed the detection of state-dependent access to deep pore position and activation-associated conformational changes in the channel pore (Salazar et al, 2009). Many informative studies on individual point mutations have been reported (Winter et al, 2013). Some of them are discussed in the rest of this chapter.…”

Tyrosine Residue in the TRPV1 Vanilloid Binding Pocket Regulates Deactivation Kinetics

“…Although efforts to elucidate the molecular basis of these sensory processes have identified several amino acids in the TRPV1 protein that participate in vanilloids binding and subsequent channel gating (15,17,19), their mechanism(s) of action remained largely unknown. Here, we analyzed the role of a conserved tyrosine, Tyr 511 in the rTRPV1 sequence, in the vanilloid-evoked response.…”

“…Although endovanilloids (such as the endocannabinoids anandamide, N-arachidonoyl dopamine (NADA), and lipoxygenase products of arachidonic acid) have been identified as TRPV1 agonists (12, 13), its most known and studied activator is the exovanilloid capsaicin, the "hot" ingredient in chili peppers (14). However, although elucidating this ligandreceptor interaction will provide a better understanding of the mechanism underlying noxious stimuli detection in the pain pathway, the molecular basis of vanilloids-mediated TRPV1 activation and deactivation is not fully understood.Since TRPV1 cloning in 1997 (3), several residues that participate in its vanilloid-mediated activation have been identified (15)(16)(17)(18)(19). The identification of these residues, mainly through site-directed mutagenesis analyses, laid the basis for the ever increasing body of studies aiming to elucidate various aspects of this important receptor (20 -22).…”

“…Since TRPV1 cloning in 1997 (3), several residues that participate in its vanilloid-mediated activation have been identified (15)(16)(17)(18)(19). The identification of these residues, mainly through site-directed mutagenesis analyses, laid the basis for the ever increasing body of studies aiming to elucidate various aspects of this important receptor (20 -22).…”