In the excitable systems of eukaryotes cells, Voltage-gated sodium channels play a predominant role in initiating and propagating electrical signalling ("action potential"). The sodium channel protein is a single polypeptide chain made up of around 2000 amino acids which folds up to form four homologous domains, termed I-IV. Each domain is constituted of six transmembrane segments, of which four (S1-S4) are designed to function as "Voltage-sensing domain" (VSD) and regulate the ion permeation. The VSD in turn surrounds the other two segments (S5-S6) thus forming the ion-conducting central pore. This channel is a target for natural toxins (batrachotoxin, µ-conotoxin) and drugs such as antiepiletics, local anesthetic and antiarrhytmic that block sodium currents. The voltage-gated sodium channel gene family comprises nine homologous members. The SCN4A gene encodes the ?-subunit of the human skeletal muscle voltage-gated sodium channel (NaV1.4). Mutations in the sodium channel can produce severe alterations known as channelopathies, which cause myotonia and muscle paralysis. Currently there is no crystalline structure of the human sodium channel. However the recent determination by means of cryo-EM (cryoelectron microscopy) of the eukaryotic structure of the Electrophorus electricus, having 77% of homology with the human one, has allowed us to reconstruct the human model transmembrane segment by homology. The work done by our group is directed towards obtaining and enhancing the homology of human NaV1.4 wild type. Preliminary docking studies on drugs, known for their analgesic and antiepileptic activity on the transmembrane segments, have confirmed their interactions with the sodium channel. Further developments of our studies will be aimed at improving the structure of the human NaV1.4 through molecular dynamics experiments. We will also investigate the mutations involved in various diseases related to human NaV1.4
Sodium channel: homology modelling, docking and molecular dynamics study of human skeletal muscle transmembrane segments
R Dallocchio;
2018
Abstract
In the excitable systems of eukaryotes cells, Voltage-gated sodium channels play a predominant role in initiating and propagating electrical signalling ("action potential"). The sodium channel protein is a single polypeptide chain made up of around 2000 amino acids which folds up to form four homologous domains, termed I-IV. Each domain is constituted of six transmembrane segments, of which four (S1-S4) are designed to function as "Voltage-sensing domain" (VSD) and regulate the ion permeation. The VSD in turn surrounds the other two segments (S5-S6) thus forming the ion-conducting central pore. This channel is a target for natural toxins (batrachotoxin, µ-conotoxin) and drugs such as antiepiletics, local anesthetic and antiarrhytmic that block sodium currents. The voltage-gated sodium channel gene family comprises nine homologous members. The SCN4A gene encodes the ?-subunit of the human skeletal muscle voltage-gated sodium channel (NaV1.4). Mutations in the sodium channel can produce severe alterations known as channelopathies, which cause myotonia and muscle paralysis. Currently there is no crystalline structure of the human sodium channel. However the recent determination by means of cryo-EM (cryoelectron microscopy) of the eukaryotic structure of the Electrophorus electricus, having 77% of homology with the human one, has allowed us to reconstruct the human model transmembrane segment by homology. The work done by our group is directed towards obtaining and enhancing the homology of human NaV1.4 wild type. Preliminary docking studies on drugs, known for their analgesic and antiepileptic activity on the transmembrane segments, have confirmed their interactions with the sodium channel. Further developments of our studies will be aimed at improving the structure of the human NaV1.4 through molecular dynamics experiments. We will also investigate the mutations involved in various diseases related to human NaV1.4I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
