Ion Channels and Their Functions

Ion Channels

• Definition: pore-forming membrane proteins associated with the transport of specific ions in or out of the cell.
• Functions:
  • Conductance of nerve impulse.
  • Generation of action potential.
  • Synaptic transmission.
  • Cardiac, skeletal, and smooth muscle contraction.
  • Controlling the flow of ions across membranes.

Classification of Ion Channels

• Based on the type of ions for which they are permeable.
• Based on the type of stimulus that triggers their activation.
• Classification by stimulus:
  • Voltage-gated ion channels: open following a change in the membrane voltage potential.
  • Ligand-gated ion channels: allow ions to flow across the pore in response to the binding of a chemical messenger (ligand) to the cytoplasmic or extracellular side of the channel.
  • Temperature-gated ion channels: represented by thermo-sensitive ion channels that belong to the transient receptor potential channel family.
  • Light-gated ion channels: found in green algae and are named channelrhodopsin-1 and -2.
  • Mechanically-gated ion channels: detect mechanical stimulation such as tension, pressure, stretch, and cell volume change.

Voltage-Gated Ion Channels

• Voltage sensitive.
• Conformational change occurs in response to the potential gradient.
• Distributed along the axon and soma of the neurons.
• Structure:
  • Each subunit is composed of six transmembrane helices named S1-S6 flanked by intracellular N and C termini.
  • S1-S4 forms the voltage-sensor domain (VSD) with a positively charged S4.
  • S5-S6 forms the pore domain with the selectivity filter that discriminates the ions.
  • Four subunits tetramerize to form an ion channel with a central pore-forming unit surrounded by four VSDs.
• Gating dynamics:
  • A voltage-gated ion channel can be in three states: closed, open, or inactivated.
  • Opening of the channel pore leads to the flow of ions according to the electrochemical gradient across the membrane.
  • The channels go from a closed state (non-conducting) to an open-state (permeable to ions) as a result of a conformational change in the pore.
  • Following activation, the channels go through an inactivated state during which the channel is non-conducting and refractory to open, so-called inactivation.

Types of Voltage-Gated Ion Channels

• Voltage-gated sodium channels: responsible for membrane depolarization in action potential.
• Voltage-gated potassium channels: responsible for membrane repolarization in action potential.
• Voltage-gated calcium channels: play an important role in linking muscle excitation with contraction as well as neuronal excitation with neurotransmitter release.
• Hyperpolarization-activated cyclic nucleotide-gated channel: pacemaking channels in the heart, sensitive to cAMP, cGMP that alter the voltage sensitivity of the channels.
• Voltage-sensitive proton channels: strongly pH-regulated that helps in acid extrusion from cell and phagocytosis.

Voltage-Gated Sodium Channels

• Expressed in all excitable tissues.
• Responsible for the rapid membrane depolarization during the action potential.
• Activation and inactivation are voltage-dependent, very fast processes (1-10 ms).
• Important targets for drugs, e.g., local anesthetics.

Voltage-Gated Potassium Channels

• Found in almost all living organisms.
• Conduct rapidly and selectively K+ ions down their electrochemical gradient.
• Responsible for membrane repolarization in action potential.
• One of the key components in generation and propagation of electrical impulses in nervous system and in the heart.

Voltage-Gated Calcium Channels (VGCCs)

• Found in the membrane of excitable cells as muscle, glial cells, and neurons with a permeability to Ca+2.
• Slightly permeable to Na+ (also called Ca+2-Na+ channels), but their permeability to Ca+2 is about 1000-fold greater.
• At resting membrane potential, VGCCs are normally closed.
• Activated (opened) at depolarized membrane potentials.
• Activation of particular VGCCs allows Ca+2 to rush into the cell, which depending on the cell type, results in:
  • Activation of calcium-sensitive potassium channels.
  • Muscular contraction.
  • Excitation of neurons.
  • Up-regulation of gene expression.
  • Or release of hormones or neurotransmitters.

Types of VGCCs

• L-type: found in skeletal muscle, smooth muscle, bone, ventricular myocytes (responsible for prolonged action potential in cardiac cell), dendrites and dendritic spines of cortical neurons.
• P-type: found in Purkinje neurons in the cerebellum and cerebellar granule cells.
• N-type: found throughout the brain and peripheral nervous system.
• R-type: found in cerebellar granule cells and other neurons.
• T-type: found in neurons, bone.

Ligand-Gated Ion Channels (LGIC) or Ionotropic Receptors

• A group of transmembrane ion-channel proteins which open to allow ions to pass through the membrane in response to the binding of a chemical messenger (ligand) such as a neurotransmitter.
• Structure: two domains; transmembrane domain including channel pore and extracellular domain including ligand binding site.
• Function: conversion of presynaptic chemical signal into post-synaptic electrical signal to elicit a cellular response.
• Examples: receptors for acetylcholine and glutamate.

Biological Implications of Ion Channels

• Action potential:
  • Definition: nerve signals.
  • Phases: hypopolarization, depolarization, overshoot, repolarization, and hyperpolarization.
• Therapeutic applications:
  • Different medical conditions have been attributed to ion channel dysfunction.
  • Examples for drugs targeting ion channels:
    • Lidocaine: local anesthetic, sodium channel blocker.
    • Verapamil: antihypertensive, calcium channel blocker.
• Ion channel dysfunction and diseases:
  • Channelopathies: diseases caused by disturbed function of ion channel subunits or the proteins that regulate them.
  • Examples:
    • Cystic fibrosis: caused by mutations in the CFTR gene, which encodes the chloride channel.
    • Brugada syndrome: a ventricular arrhythmia caused by mutation in SCN5A, which encodes the cardiac sodium channel.
    • Episodic ataxia: caused by mutations in KCNA1 gene, which encodes the voltage-gated potassium channel.