Question

How were voltage-gated sodium channels that may be better targets for developing more precise painkillers discovered?

Answer 1

1. Voltage gated sodium channels are large transmembrane proteins that conduct the flow of sodium ions down the electrochemical gradient through cell membranes. These channels control the initiation and propagation of action potential. In excitable and non excitable cells these channels control the initiation of action potential, cell motility and proliferation.

2. Ion channel targeted drugs have there effect on the central nervous system (CNS), the peripheral nervous system, or the cardiovascular system. Within the CNS, basic indications of drugs are: sleep disorders, anxiety, epilepsy, pain, etc

3. Traditional channel blockers have multiple adverse effects, mainly due to low specificity of mechanism of action. The discovery of novel ion channel subtypes, gives premises to drug discovery process .

4. The voltage-gated sodium channels (VGSCs) are heteromeric transmembrane proteins which open in response to alteration in membrane potential to provide selective permeability for sodium ions Sodium channels are built by several subunits. Subunit α forms a Na+ selective pore. It has molecular mass of 260 kDa. It consists of four homologous domains (I-IV or D1-D4), of which each contains six α-helical transmembrane segments (S1-S6) and one non-helical relatively short re entrant segment (SS1/SS2), known also as the P-segment, located between S5 and S6. All segments and domains are connected by internal or external polypeptide loops. The S4 segments are positively charged due to presence of positively charged amino acid residues and their role is to initiate the voltage-dependent activation of sodium channels by moving outward while influenced by the electric field. Therefore, S4 segments serve as voltage sensors. The short intracellular loop connecting domains III and IV occlude the cytoplasmic end of the pore when channel inactivates. The membrane reentrant loops between S5 and S6, which are the part of P-segment form the ion selectivity filter and ion pathway as well as the outer region of the pore.

5. Sodium channels possess also one or more β-subunits of about 35 kDa. The role of β-subunits is influencing the properties of α-subunits including modulation of sodium currents. Moreover, they function as cell adhesion molecules and play role in aggregation, migration as well as cell surface expression.

6. β-subunits typically possess a large extracellular immunoglobulin-like N-terminal domain, a single transmembrane region and intracellular C-terminal region. α- and β-subunits are associated non-covalently (α with β1 or β3) or covalently, e.g. by means of disulfide bond (α with β2 or β4).

7. Sodium channels are the molecular target of many neurotoxins,for example, tetrodotoxin and saxitoxin bind to site 1 (domains I SS2-S6, II SS2-S6, III SS2-S6, and IV SS2-S6), batrachotixin, veratridine and aconitine to site 2 (domain IS6), α-scorpion toxins to site 3 (I S5-S6), β-scorpion toxins to site 4, DDT site 7, common anticonvulsants and local anesthetics bind to site 9. Binding to specific site of the receptor is related with a defined physiologal effect, direct affecting of ion transport is characteristic for sites 1 and 9 and modification of gating process with sites 2-8 .

8. VGSCs blockers act through different sites of α-subunit but no drugs are known to interact directly with β-subunit.