Consequences of phosphate-arginine complexes in voltage gated ion channels

Abstract

There are two reasons for suspecting that phosphate complexes of arginine make it very difficult to derive gating charge in voltage gated potassium (and presumably sodium) channels from the motion of charged arginines. For one thing, the arginines should be complexed with phosphate, thereby neutralizing the charge, at least partially. Second, Li et al. 1 have shown that there is a large energy penalty for putting a charged arginine into a membrane. Ion channel gating current is generally attributed to S4 motion, in that the S4 segment of the voltage sensing domain (VSD) of these channels contains arginines, some of which are not (or at least not obviously) salt bridged, or otherwise charge compensated. There is, however, good reason to expect that there should be a complex of these arginines with phosphate, very probably from lipid headgroups. This has consequences for gating current; the complexed arginines, if they moved, would carry too much of the membrane along. This leads to the suggestion that an alternative to S4 physical motion, H + transport, should be considered as a possible resolution of the apparent paradox. The consequences for a gating model that was proposed in our earlier work are discussed; there is one major difference in the model in the present form (a conformational change), but the proton cascade as gating current and the role of water in the closed state are reinforced.

Preferential selection of Arginine at the lipid-water-interface of TRPV1 during vertebrate evolution correlates with its snorkeling behaviour and cholesterol interaction

“…Cholesterol and/or membrane deformations are known to stabilize Arg residues in its protonated form in the LWI and thereby can cause a shift in the pKa of Arg 68 . Such stabilization of Arg residues at the LWI can significantly alter the biophysical properties of ion channels and other transmembrane proteins 22 , 69 , 70 . The peptide sequences corresponding to the different transmembrane regions are certainly selected throughout the evolution.…”

The Role of Proton Transport in Gating Current in a Voltage Gated Ion Channel, as Shown by Quantum Calculations

“…While evidence that PIP2 is involved in complexing arginine in channels has not been reported (yet), this would be consistent with the existence of phosphate-arginine complexes; so far, a complete proof awaits further evidence. However, calculations [ 90 , 91 ] and experiment [ 92 , 93 ] both show that guanidinium and phosphate form complexes that are fairly stable. Therefore, the end arginine, which reaches into the headgroup region, would be complexed with phosphate, with high probability.…”

Quantum Calculations Of A Large Section Of The Voltage Sensing Domain Of The Kv1.2 Channel Show That Proton Transfer, Not S4 Motion, Provides The Gating Current

“…At least some negative charges must exist in the membrane to have a functioning channel 62 , and the mechanical state of the membrane also matters 63 ; this seems unlikely if S4 simply went through it. Arginines form fairly strong complexes with phosphates [64][65][66][67] , which would anchor R294, making a fixed position of S4 unavoidable. R294 is omitted in this calculation, as its side chain is unattached to the rest of the system.…”