Structure of voltage-gated ion channels

Question 1

What is the general structural topology of voltage-gated ion channels?

Answer 1

Voltage-gated ion channels are formed by either one α-subunit that is a contiguous polypeptide that contains four repeats (domains I–IV), as in the case of Nav and Cav channels; or four α-subunits, each with a single domain, as in the case of Kv and HCN channels.

A single domain contains six α helical transmembrane (TM) segments.

The fourth TM segment contains multiple arginines that are mainly responsible for sensing changes in membrane potential. Between the fifth and sixth TM segments is a re-entrant pore loop, which forms the narrowest part of the pore.

Question 2

Which auxiliary subunits co-assemble with the Nav α-subunit?

Answer 2

There are four known Nav protein β-subunits (β1, β2, β3, β4), each with a single transmembrane segment and an extracellular domain that is structurally homologous to the immunoglobulin G-like domains of L1 cell-adhesion molecules (L1 CAMs).

Question 3

How many Kv channel α-subunits families are there?

Answer 3

The Kv channel α-subunits are grouped into 12 families known as Kv1 to Kv12

Question 4

Which auxiliary subunits co-assemble with the Kv α-subunit and how?

Answer 4

Kv1 α-subunits associate with the β-subunits Kvβ1.1, Kvβ1.2, Kvβ2 and Kvβ3 through their N-terminal T1 domains, with an α4:β4 stoichiometry.

Kv4 subunits are associated with KChIPs, calcium-binding
proteins that bind to the N-terminus of Kv4 channels, and DPPX, a single transmembrane-spanning protein in which the extracellular domain resembles a dipeptidyl aminopeptidase, as well as the cell adhesion protein CD26.

Question 5

How are Cav channels subdivided?

Answer 5

Cav channels are subdivided into groups based on which current type they give rise to:

Cav1 - L-type current.

Cav2.1 - P/Q-type current

Cav2.2 - N-type current

Cav2.3 - R-type current

Cav3 - T-type current

Question 6

Which auxiliary subunits are Cav channels associated with?

Answer 6

Cav channels are associated with
several auxiliary subunits in vivo that affect channel function and expression:
a cytosolic β-subunit, a disulphide-linked α2δ complex and an occasional γ-subunit, which create an α1α2δβγ native Cav channel