Anti-calmodulins and Tricyclic Adjuvants in Pain Therapy Block the TRPV1 Channel
Figure 10
(a) Homologous portions of various TRP channels, near the border of the pore loop and the 6th transmembrane domain were aligned with a validated R4W2 peptide similar in biochemical character to ruthenium red.
An acidic tetrad motif DXEXXEXXD which can bind the positively charged peptides in human and rat TRPV1, is absent in TRPV2/VRL1 and TRPV3, (both close homologues of TRPV1) as well as in distantly related TRPs and bKcsA, a bacterial cation channel. An acidic sequence, partially similar to the heat sensitive TRPs, is present in the cold responsive TRPM8/CMR1. Distant TRPV homologues do not share the acidic tetrad motif either, such as g/mOTRPC4 and hOSM, nonselective cation channel orthologues from Gallus gallus (chicken), mouse, and human, respectively that confer sensitivity to extracellular osmolarity, mTRP12, another osmotically activated TRP channel from mouse; mGFRCC, mouse growth factor receptor coupled channel; hVOC, Homo sapiens Kv4.3 potassium channel; dSha12, a “shaker-like” potassium channel from Drosophila melanogaster. (b) The TM5-pore loop-TM6 region of TRPV1 is analogous to the “inverted teepee”, pore-forming domain of bKcsA. Side-view of the TRPV1 tetramer channel depicts the hypothetical pore at the middle. Arrows point to the putative ruthenium red/R4W2 binding site in each TRPV1 subunits of the tetramer. (c) To better represent the simulated quaternary structure of TRPV1, a view perpendicular to the plasma membrane is generated with the homo-tetrameric TRPV1 domain fragments. The position of acidic domain is noted by an arrow in a single subunit in this view of the model.