Molecular pathophysiology and pharmacology of the voltage-sensing module of neuronal ion channels

Abstract

Voltage-gated ion channels (VGICs) are membrane proteins that switch from a closed to open state in response to changes in membrane potential, thus enabling ion fluxes across the cell membranes. The mechanism that regulate the structural rearrangements occurring in VGICs in response to changes in membrane potential still remains one of the most challenging topic of modern biophysics. Na+, Ca2+ and K+ voltage-gated channels are structurally formed by the assembly of four similar domains, each comprising six transmembrane segments. Each domain can be divided into two main regions: the Pore Module (PM) and the Voltage-Sensing Module (VSM). The PM (helices S5 and S6 and intervening linker) is responsible for gate opening and ion selectivity; by contrast, the VSM, comprising the first four transmembrane helices (S1–S4), undergoes the first conformational changes in response to membrane voltage variations. In particular, the S4 segment of each domain, which contains several positively charged residues interspersed with hydrophobic amino acids, is located within the membrane electric field and plays an essential role in voltage sensing. In neurons, specific gating properties of each channel subtype underlie a variety of biological events, ranging from the generation and propagation of electrical impulses, to the secretion of neurotransmitters and to the regulation of gene expression. Given the important functional role played by the VSM in neuronal VGICs, it is not surprising that various VSM mutations affecting the gating process of these channels are responsible for human diseases, and that compounds acting on the VSM have emerged as important investigational tools with great therapeutic potential. In the present review we will briefly describe the most recent discoveries concerning how the VSM exerts its function, how genetically inherited diseases caused by mutations occurring in the VSM affects gating in VGICs, and how several classes of drugs and toxins selectively target the VSM.

Clinical Spectrum of KCNA1 Mutations: New Insights into Episodic Ataxia and Epilepsy Comorbidity

“…Each Kv α-subunit has six transmembrane (TM) spanning segments (helices S1-S6) that include the functionally critical voltage-sensing and pore domains. Helices S1-S4 form the voltage-sensing domain of the protein, with S4 playing a specifically important role as the voltage sensor [59]. Evenly spaced positive charges across S4 allow this helix to acutely sense changes in voltage across the membrane; together with S3, these helices form a voltage sensor paddle that can change conformation to alter the state of the channel [59][60][61].…”

“…Helices S1-S4 form the voltage-sensing domain of the protein, with S4 playing a specifically important role as the voltage sensor [59]. Evenly spaced positive charges across S4 allow this helix to acutely sense changes in voltage across the membrane; together with S3, these helices form a voltage sensor paddle that can change conformation to alter the state of the channel [59][60][61]. The pore region of the channel, which allows ion flux through the membrane, is formed by S5 and S6 [50].…”

“…The pore region of the channel, which allows ion flux through the membrane, is formed by S5 and S6 [50]. The S4-S5 intracellular linker communicates changes in the voltage-sensing domain to the pore domain and thus can initiate a shift between the open and closed states of the pore [59,61]. The intracellular N-and C-terminal domains of each Kv α-subunit also regulate channel function.…”

Therapeutic Approaches to Genetic Ion Channelopathies and Perspectives in Drug Discovery

“…Moreover, inward rectifier potassium channels contribute to the maintenance of resting potential and to the transport and buffering of K + across membranes. Thus, disruption of K + channels in specific brain areas is often associated with increased susceptibility to seizures (for reviews see D’Adamo et al, 2015b ; Miceli et al, 2015a ). Patients affected by episodic ataxia type 1, a form of episodic ataxia with myokymia (see below) caused by loss-of-function mutations in KCN1A (coding for K v 1.1 channel), often report abnormal EEGs, and several animal models carrying kcna1 gene defects show an increased susceptibility to seizures ( Smart et al, 1998 ).…”

“…Loss- and gain-of-function mutations in KCNA2 (encoding the potassium channel K v 1.2) have been identified in patients with epileptic encephalopathy, intellectual disability, delayed speech development and sometimes ataxia ( Syrbe et al, 2015 ). Loss-of-function mutations in KCNQ2 or KCNQ3 (encoding for K v 7.2 and K v 7.3 channels) cause Benign Familial Neonatal Convulsions (BFNC; prevalence: 100 reported families), a form of juvenile epilepsy characterized by tonic or clonic episodes spontaneously disappearing during the first year of life ( Miceli et al, 2015a ). In the brain, heteromeric channels composed of K v 7.2 and K v 7.3 subunits underlie the M-current that regulates neuronal excitability in the sub-threshold range for action potential generation and limits repetitive firing ( Soldovieri et al, 2011 ).…”