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How do ion channels work?

 

As mentioned in our previous article, until 1998 it was impossible to study the detailed structure of ion channels. But thanks to X-ray crystallography, Rod Mackinnon and colleagues succeeded in solving the structure of a K+ channel (Doyle et al. 1998), rapidly unlocking the understanding of ion channel functional mechanisms.

 

Wrongly considered at first as moving ferries carrying ions, ion channels are selective macromolecular pores in cell membranes that allow a tightly regulated movement of ions along their electrochemical gradient. The intensity and the direction of ion movement is based on electrochemical gradient, but also on the ease with which the ion can move through the pore, what we name the permeability of the channel for a selective ion.

 

Electrochemical gradient is influenced by the ion concentration on each side of the membrane, but also by the electric field since ions are charged particles. Regarding the permeability, several factors play a role, but one that must be considered is the relative size of the pore and the ion: large ions are physically unable to permeate small pores.

 

An ion channel not only select and conduct ions, but also activate and deactivate on a millisecond time scale. Either open or closed, ion channel receptors transit from one state to another, what is called the gating phase. Depending on their gating mechanisms, three types of ion channels are described:

 

Voltage Independent Ion Channels

 

Such channels open randomly at all membrane potentiels.

 

Voltage-Gated Ion Channels

 

Such transmembrane proteins respond to fluctuations of cell membrane potentials related to specific ions Na+, K+, Ca2+, and Cl-, that permit ion channels normally closed to open.

 

Ligand-Gated Ion Channels

 

Such ion channels - may be extracellular (neurotransmitters acetylcholine and glycine) or intracellular (cAMP and ATP) -accept a ligand that produces a conformational change of their receptor and opens the ion channel pore. These transmembrane proteins are the most studied of the ion channel family as drug targets and can be found in various subfamilies:

 

“Cys-Loop” Ligand-Gated Ion Channels

 

Pentameric structures like:

  • Nicotinic acetylcholine receptors (nAChR). Neuro-muscular junction and neuronal synapses are the locations of these receptors that can be activated by nicotine, choline and acetylcholine inducing an influx of Na+, K + and Ca2+ cations.
  • γ-aminobutyric acid (GABA) receptors. Located in the brain, the binding of GABA triggers anion influx causing cell membrane hyperpolarization and signal inhibition while its antagonist, bicuculline, induces excitation.
  • 5-hydroxytryptamine-3 (5HT3) receptors. All the seven 5-HT receptors with the exception of 5- HT3 are metabotropic receptors and are found in central nervous system.
  • Glycine receptors. The distribution of glycine receptors is mainly in the brain stem and spinal cord where by mediating Cl- conductance they play an inhibitory role.

Ionotropic Glutamate Ligand-Gated Ion Channels

 

Tetrameric structures mediated by glutamate neurotransmitter, like:

  • α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors. The four subunits GluR1, 2, 3, 4 (A-D) of AMPA receptor are located in the brain where they are involved in the process of learning and memory. The channel is non-selectively permeable to cations like Na+, K + and Ca2+. Cation influx into the cell induces membrane depolarization and leads to cell excitation.
  • N-methyl-D-aspartate (NMDA) receptors. Gating of NDMA ion channel is regulated by glycine and glutamate binding to the GluN1 and GluN2 subunits and the ion flow is dependent on membrane voltage created by Mg2+ and Zn2+.
  • kainic acid receptors (KARs) like GluR5-7, KA1, 2

ATP-gated P2X receptor cation channel family

 

Trimeric structures activated by extracellular adenosine 5'-triphosphate, they are widely expressed in many tissues in a variety of organisms. Purinergic P2X receptor or purinoreceptors are involved in cell proliferation, cytokine secretion and apoptosis due to Ca2+ influx. There are seven subtypes of P2X receptors – P2X1 to P2X7 - and they can form heteromultimer associations.

 

Once a single ion channel allows ion movement across the membrane, from the inside or the outside of the cell, it alters the charge on both sides of the bilipid layer. The differential of charge induces adjacent ion channels to open and so trigger a domino effect to the entire cell.

 

And what began as a single-channel signal quickly becomes a complex cascade of downstream events.