@article{MTMT:33860361, title = {Cinacalcet inhibition of neuronal action potentials preferentially targets the fast inactivated state of voltage-gated sodium channels}, url = {https://m2.mtmt.hu/api/publication/33860361}, author = {Lindner, Jamie S. S. and Rajayer, Salil R. R. and Martiszus, Briana J. J. and Smith, Stephen M. M.}, doi = {10.3389/fphys.2022.1066467}, journal-iso = {FRONT PHYSIOL}, journal = {FRONTIERS IN PHYSIOLOGY}, volume = {13}, unique-id = {33860361}, abstract = {Voltage-gated sodium channel (VGSC) activation is essential for action potential generation in the brain. Allosteric calcium-sensing receptor (CaSR) agonist, cinacalcet, strongly and ubiquitously inhibits VGSC currents in neocortical neurons via an unidentified, G-protein-dependent inhibitory molecule. Here, using whole-cell patch VGSC clamp methods, we investigated the voltage-dependence of cinacalcet-mediated inhibition of VGSCs and the channel state preference of cinacalcet. The rate of inhibition of VGSC currents was accelerated at more depolarized holding potentials. Cinacalcet shifted the voltage-dependence of both fast and slow inactivation of VGSC currents in the hyperpolarizing direction. Utilizing a simple model, the voltage-dependence of VGSC current inhibition may be explained if the affinity of the inhibitory molecule to the channel states follows the sequence: fast-inactivated > slow-inactivated > resting. The state dependence of VGSC current inhibition contributes to the non-linearity of action potential block by cinacalcet. This dynamic and abundant signaling pathway by which cinacalcet regulates VGSC currents provides an important voltage-dependent mechanism for modulating central neuronal excitability.}, keywords = {sodium channel; action potential; cinacalcet; CaSR; Calcium-sensing receptor; voltage-gated sodium channel}, year = {2022}, eissn = {1664-042X} } @article{MTMT:32366085, title = {Pharmacological and nutritional targeting of voltage-gated sodium channels in the treatment of cancers}, url = {https://m2.mtmt.hu/api/publication/32366085}, author = {Lopez-Charcas, Osbaldo and Pukkanasut, Piyasuda and Velu, Sadanandan E. and Brackenbury, William J. and Hales, Tim G. and Besson, Pierre and Carlos Gomora, Juan and Roger, Sebastien}, doi = {10.1016/j.isci.2021.102270}, journal-iso = {ISCIENCE}, journal = {ISCIENCE}, volume = {24}, unique-id = {32366085}, abstract = {Voltage-gated sodium (Na-V) channels, initially characterized in excitable cells, have been shown to be aberrantly expressed in non-excitable cancer tissues and cells from epithelial origins such as in breast, lung, prostate, colon, and cervix, whereas they are not expressed in cognate non-cancer tissues. Their activity was demonstrated to promote aggressive and invasive potencies of cancer cells, both in vitro and in vivo, whereas their deregulated expression in cancer tissues has been associated with metastatic progression and cancer-related death. This review proposes Na-V channels as pharmacological targets for anticancer treatments providing opportunities for repurposing existing Na-V-inhibitors or developing new pharmacological and nutritional interventions.}, year = {2021}, eissn = {2589-0042}, orcid-numbers = {Lopez-Charcas, Osbaldo/0000-0002-5080-8310} } @article{MTMT:31244580, title = {Substituted cysteine scanning in D1-S6 of the sodium channel hNav1.4 alters kinetics and structural interactions of slow inactivation}, url = {https://m2.mtmt.hu/api/publication/31244580}, author = {Beard, Jonathan M. and Shockett, Penny E. and O'Reilly, John P.}, doi = {10.1016/j.bbamem.2019.183129}, journal-iso = {BBA-BIOMEMBRANES}, journal = {BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES}, volume = {1862}, unique-id = {31244580}, issn = {0005-2736}, abstract = {Slow inactivation in voltage-gated Na+ channels (Nays) plays an important physiological role in excitable tissues (muscle, heart, nerves) and mutations that disrupt Nay slow inactivation can result in pathophysiologies (myotonia, arrhythmias, epilepsy). While the molecular mechanisms responsible for slow inactivation remain elusive, previous studies have suggested a role for the pore-lining D1-S6 helix. The goals of this research were to determine if (1) cysteine substitutions in D1-S6 affect gating kinetics and (2) methanethiosulfonate ethylammonium (MTSEA) accessibility changes in different kinetic states. Site-directed mutagenesis in the human skeletal muscle isoform hNav1.4 was used to substitute cysteine for eleven amino acids in D1-S6 from L433 to L443. Mutants were expressed in HEK cells and recorded from with whole-cell patch clamp. All mutations affected one or more baseline kinetics of the sodium channel, including activation, fast inactivation, and slow inactivation. Substitution of cysteine (for nonpolar residues) adjacent to polar residues destabilized slow inactivation in G434C, F436C, I439C, and L441C. Cysteine substitution without adjacent polar residues enhanced slow inactivation in L438C and N440C, and disrupted possible H-bonds involving Y437:D4 S4-S5 and N440:D4-S6. MTSEA exposure in closed, fast-inactivated, or slow-inactivated states in most mutants had little-to-no effect. In I439C, MTSEA application in closed, fast-inactivated, and slow-inactivated states produced irreversible reduction in current, suggesting I439C accessibility to MTSEA in all three kinetic states. D1-S6 is important for Nay gating kinetics, stability of slow-inactivated state, structural contacts, and state-dependent positioning. However, prominent reconfiguration of D1-S6 may not occur in slow inactivation.}, keywords = {SLOW INACTIVATION; D1-S6; hNav1.4; Gating kinetics; Cysteine-substituted mutants; SCAM}, year = {2020}, eissn = {1879-2642} } @article{MTMT:31747152, title = {Variable patterns of mutation density among Na(V)1.1, Na(V)1.2 and Na(V)1.6 point to channel-specific functional differences associated with childhood epilepsy}, url = {https://m2.mtmt.hu/api/publication/31747152}, author = {Encinas, Alejandra C. and Watkins, Joseph C. and Longoria, Iris Arenas and Johnson, J. P. Jr. and Hammer, Michael F.}, doi = {10.1371/journal.pone.0238121}, journal-iso = {PLOS ONE}, journal = {PLOS ONE}, volume = {15}, unique-id = {31747152}, issn = {1932-6203}, abstract = {Variants implicated in childhood epilepsy have been identified in all four voltage-gated sodium channels that initiate action potentials in the central nervous system. Previous research has focused on the functional effects of particular variants within the most studied of these channels (Na(V)1.1, Na(V)1.2 and Na(V)1.6); however, there have been few comparative studies across channels to infer the impact of mutations in patients with epilepsy. Here we compare patterns of variation in patient and public databases to test the hypothesis that regions of known functional significance within voltage-gated sodium (Na-V) channels have an increased burden of deleterious variants. We assessed mutational burden in different regions of the Na(v)channels by (1) performing Fisher exact tests on odds ratios to infer excess variants in domains, segments, and loops of each channel in patient databasesversuspublic "control" databases, and (2) comparing the cumulative distribution of variant sites along DNA sequences of each gene in patient and public databases (i.e., independent of protein structure). Patient variant density was concordant among channels in regions known to play a role in channel function, with statistically significant higher patient variant density in S4-S6 and DIII-DIV and an excess of public variants in SI-S3, DI-DII, DII-DIII. On the other hand, channel-specific patterns of patient burden were found in the Na(V)1.6 inactivation gate and Na(V)1.1 S5-S6 linkers, while Na(V)1.2 and Na(V)1.6 S4-S5 linkers and S5 segments shared patient variant patterns that contrasted with those in Na(V)1.1. These different patterns may reflect different roles played by the Na(V)1.6 inactivation gate in action potential propagation, and by Na(V)1.1 S5-S6 linkers in loss of function and haploinsufficiency. Interestingly, Na(V)1.2 and Na(V)1.6 both lack amino acid substitutions over significantly long stretches in both the patient and public databases suggesting that new mutations in these regions may cause embryonic lethality or a non-epileptic disease phenotype.}, year = {2020}, eissn = {1932-6203} }