Ion Channels and Their Functions

Ion Channels and Voltages

Ion Channels

• Definition: Pore-forming membrane proteins associated with 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
• Selectivity: Ion channel selectivity discriminates cations (Na+, K+, Ca+) from anions (Cl-), and allows selectivity among cations (Na+, K+, Ca+)
• Classification can be based on:
  • Type of ions for which they are permeable
  • Type of stimulus that triggers their activation

Classification of Ion Channels Based on 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: Able to 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:
  • 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
  • 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

Ligand-Gated Ion Channels

• Definition: 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 Implication of Ion Channels

• Action potential:
  • Definition: Nerve signals generated and conducted by neurons to transmit to target tissues
  • 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 (sodium channel blocker) and Verapamil (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, Brugada syndrome, and Episodic ataxia