Role of hydrophobic residues in the voltage sensors of the voltage-gated sodium channel

The role of hydrophobic residues in voltage sensors S4 of voltage-sensitive ion channels is less documented than that of charged residues. We performed alanine-substitution of branched-sidechain residues contiguous to the third, fourth and fifth positively charged residues in S4s of the first three domains of the sodium channel expressed in HEK cells. These locations were selected because they are close to the arginines and lysines important in gating. Mutations in the first two domains (DIS4 and DIIS4) altered steady-state activation curves. In DIIIS4, the mutation L1131A next to the third arginine greatly slowed inactivation in a manner similar to that for substitutions of charged residues in DIVS4, whereas the mutation L1137A next to the fifth arginine preserved wild-type behaviour. Homology models of domain III, based on the structure of a crystallized mammalian potassium channel, shows that L1131 is located at the interface between S3 and S4 helices, whereas L1137, on the opposite side of S4, does not interact with the voltage sensor. The two mutated residues are closer to each other in domains I and II than in domain III, as may be corroborated by their different electrophysiological effects

Rare neurological channelopathies — networks to study patients, pathogenesis and treatment

Each of the thousands of rare neurological diseases requires a widely distributed network of centres, investigators and patients, so as to foster multidisciplinary investigations and involve sufficient numbers of patients in the discovery of disease pathogenesis and novel treatment. In this Review, we highlight the value of this collaborative approach in patient-oriented research into rare neurological channelopathies. Two networks, the Consortium for Clinical Investigations of Neurological Channelopathies (CINCH) and the Clinical Research Consortium for Studies of Cerebellar Ataxias (CRC-SCA), provide a link between patients with rare channelopathies and investigators who are studying disease pathogenesis and developing novel treatments. Interactions between patients, researchers and advocacy groups promote shared agendas that benefit patient education and recruitment, research collaboration and funding, and training and mentoring of junior investigators who are attracted to the study of the diseases that provide the focus for the two networks. Here, we discuss how linkage of national and international centres has enabled recruitment of study participants, provided opportunities for novel studies of pathogenesis, and facilitated successful clinical trials