Voltage Gated Ion Channels

Channels (Ion Channels)

Integral membrane proteins.

Transmembrane domains

Regions of channels composed of Nonpolar (neutral) amino acid side chains.

Core domain

Regions of channels composed of Polar (charged) amino acid side chains.

Diffusion

Movement of ions through channels created by aqueous pores.

Electrochemical Gradient

The condition that allows ions to move across a membrane.

Chemical gradient

The condition where the concentration of a particular ion is higher outside or inside the cell.

Electrical gradient

The difference in positive and negative ions between the outside and the inside of the cell.

Membrane potential

Created by the combination of cations and anions inside and outside the cell. It is always thought of as the inside relative to the outside.

Resting Membrane Potential

The steady-state condition of the membrane potential, typically ranging from -60 to -90 mV. The average resting membrane potential of neurons is -70 mV. It is determined by the combination of ion movement through the channels that are open when the cell is at rest.

Hyperpolarization

A change in membrane potential (caused by ions moving across a membrane and carrying a charge). An example is the GABAA receptor allowing Cl- to move across the membrane

Depolarization

A change in membrane potential (caused by ions moving across a membrane and carrying a charge). An example is the nicotinic acetylcholine receptor allowing Na +
and Ca2+ across the membrane

Equilibrium potential

The potential at which an ion will be at equilibrium (where the change in free energy (ΔG) is zero). The Nernst equation can be used to calculate this. The equilibrium potential of an ion determines its movement across a membrane.

Gating (of ion channels)

Refers to the regulation of membrane potential. Open and closed are relative terms referring to different conformations. The opening and closing of channels are stochastic events.

Stochastic Events

The opening and closing of channels within a membrane are considered stochastic events. Conformation changes in gated channels are also stochastic events.

Permeability

A membrane has an increased permeability for an ion when channels within the membrane are open, allowing the ion to move down its electrochemical gradient.

Voltage-gated ion channels (VGIC)

Channels whose structure and therefore function can be manipulated by compounds. They open in response to a depolarizing voltage.

Ligand-gated ion channels

Channels whose structure and therefore function can be manipulated by compounds.

Selectivity filter

The structural element that makes a channel selective for certain ions.

Ion Selectivity (basis)

Determined by the size of the ion, the hydration shell created with the aqueous environment, and the ability of the ion to favorably interact with amino acids in the pore region of the channel.

Voltage sensor

Refers to the component responsible for activation and opening of VGICs. The S4 segment acts as the voltage sensor.

Inactivated state (of VG channels)

One of the three physiological states channels exist in; they are closed and not capable of being open. The inactivation often involves a peptide interfering with the pore.

alpha-subunit

The main functional unit forming the channel of each member of the VGIC Superfamily. It typically has four domains, each with six transmembrane segments.

Expression Cloning

A technique that involves isolating RNA from tissue and creating a copy of DNA (cDNA) to study ion channels.

Recombinant Expression

Over-expressing the cDNA of interest in mammalian systems/cells (like HEK, CHO, HELA cells, or Xenopus oocytes).

Electrophysiology

A technique used to measure structure/function and pharmacology of ion channels. It is useful for determining biophysical and pharmacological properties of cells.

Patch Clamp Recording

An electrophysiology technique that includes whole cell recording and single channel recording.

Frequency or Use Dependent Block

A mechanism where Na+ channel blockers selectively block channels that are being extensively activated (high level of channel activation).

Open channel block (Pore-block)

A mechanism of action for toxins and other agents that modify VG channel function.

Channelopathies

Diseases caused by inherited mutations of ion channels, often in neurons. Pharmacological agents can be used to treat the resulting pathologies.

Late Na current

Implicated in numerous cardiac pathologies, such as Long Q-T syndrome (LQT3) and the condition called Torsade de Pointes.

Cross-Talk

Communication between receptors and ion channels. This involves signaling modulation of VGICs, often involving G-proteins.
Specific Channels and Subtypes

Na+ VG Channel

Targeted by numerous toxins and blockers; mutations cause channelopathies, such as generalized epilepsy and myotonia (__v1.1).

K+ VG Channel

Mutations linked to channelopathies (e.g., episodic ataxia (Kv1.1), benign familial neonatal convulsions (KCNQ2, KCNQ3), Long Q-T syndrome).

Ca2+ VG Channel

Mutations linked to channelopathies (e.g., familial hemiplegic migraine, episodic ataxia, spinocerebellar ataxia (__v2.1)).

Cl- VG Channel

Member of the VGIC Superfamily.

Na+ K+ pump

Contributes to maintaining the negative resting membrane potential.

GABA receptor

Allows Cl − to move across the membrane, causing hyperpolarization.

Nicotinic acetylcholine receptor

Allows Na+ and Ca2+ across the membrane, causing depolarization.

L-type Channel

High voltage activation; slow inactivation; main function is muscle contractility (cardiac, smooth & skeletal).

P/Q-type Channel

High voltage activation; moderate inactivation; main function is neurotransmitter release and neural integration.

N -type Channel

High voltage activation; current entering can be "decreased" by Gβγ binding during membrane depolarization.

R -type Channel

Intermediate voltage activation; moderate-slow inactivation; main function is neuronal activity.

T-type Channel

Low voltage activation; rapid inactivation; main function is pace making in heart & brain.

muscarinic receptor

Activation leads to K +channel opening, causing hyperpolarization that reduces heart rate, conduction velocity, and contractility.

Tetrodotoxin (TTX) (Puffer fish)

Targets Na + channels (Site 1); causes pore block. Can inhibit spontaneous action potentials.

Ziconotide

Targets N-type Ca 2+ Channel.

Resveratrol

Na + channel blocker (NaCB). Derivatives (C1) reduce atrial fibrillation duration. It may also target SIRT4 and BCaK + channels.