Findings from Condensed-State Physics on Branched-Chain Amino Acids Apply to Voltage-Sensitive Ion Channels

Abstract

Dramatic effects on channel function by mutations of branched to unbranched residues demonstrate the importance of branched-chain amino acids (BCAAs)—I, L and V—in voltage-sensitive ion channels (VSICs): L to A mutations in Shaker K channel S4 segments shift conductance-voltage curves.1 Substitution of unbranched for branched residues in fragments of Nav channels alters their voltage response.2 Mutations of L to A in S4 segments of Nav1.4 channels alters steady-state activation curves and slows inactivation.3 Voltage-sensor motion in Ci-VSP channels is tuned over two orders of magnitude or shifted 120 mV by I126 of S1.4 In a Kv channel, I237 controls the voltage dependence of charge movement, shifting the Q-V curve toward more positive voltages; I287 controls the energy barrier underlying activation.5 In 1986, Yoshino et al. investigated whether sidechains of amino acids engender ferroelectric properties in molecules with aromatic rings and chiral centers. Three of them did, dramatically: the BCAA sidechains. One compound with an isoleucine sidechain, 4'-3M2CPOOB, exhibited a ferroelectric phase with extremely large spontaneous polarization and dielectric permittivity ε over 3000.6, 7 Applying these condensed-state-physics findings to VSICs suggests that the high-electric-field resting channel is ferroelectric, with a high ε, so that the electrostatic repulsions between the positively charged arginine and lysine residues of S4 are weak. Threshold depolarization, according to the Channel Activation by Electrostatic Repulsion (CAbER) hypothesis,8 converts the channel to a nonpolar phase with much lower ε, causing these repulsions to greatly increase, which expands the S4 segments. CAbER proposes that this observed outward S4 motion drives the channel into a stochastically ion-conducting, active, conformation. 1. Lopez GA et al. (1991) Neuron 7:327-336. 2. Helluin O et al. (2001) IEEE Trans Diel Elect Insul 8:637-643. 3. Bendahhou S et al. (2007) BBA 1768:1440-1447. 4. Lacroix JJ, Bezanilla F (2012) Biophys J 103: L23-L25. 5. Lacroix JJ et al. (2014) PNAS 111(19):E1950-E1959. 6. Yoshino K et al. (1986) Japan J App Phys 25:L416-L418. 7. Yoshino K, Sakurai T (1991) In: Goodby JW et al., Ferroelectric Liquid Crystals, Gordon and Breach. 8. Leuchtag HR (2008) Voltage-Sensitive Ion Channels, Springer; (2016) Biophys J 110(3) 277a; http://doi.org/10.13140/RG.2.1.3360.2328.