Ion Channels. 6 th December, Touqeer Ahmed PhD Atta-ur-Rahman School of Applied Biosciences National University of Sciences and Technology

Transcription

1 Ion Channels 6 th December, 2016 Touqeer Ahmed PhD Atta-ur-Rahman School of Applied Biosciences National University of Sciences and Technology

2 Introduction The ion channels of nerve cells are optimally tuned for rapid information processing particularly in the brain Malfunctioning of ion channels in nerve and skeletal muscle can cause a wide variety of neurological diseases Diseases due to ion channel malfunction are not limited to the brain. Cystic fibrosis and certain types of cardiac arrhythmia, for example, are also caused by ion channel malfunction. Ion channels are often the site of action of drugs, poisons, or toxins. Thus ion channels have crucial roles in both the physiology and the pathophysiology of the nervous system.

3 Important Role of Ion Channels in the Nervous System Ion channels have three important properties: 1. They conduct ions 2. They recognize and select specific ions 3. They open and close in response to specific electrical, mechanical, or chemical signals.

4 Molecular Mechanism of Selectivity The ionic permeability and selectivity properties of the membrane are determined by the interactions of ions with water, the membrane lipid bilayer, and ion channels

5 Characteristics of the current in a single ion channel. A. The channel opens and closes in an all-or-none fashion, resulting in brief current pulses through the membrane. If the electrical potential (V m ) across the membrane is varied, the current through the channel (i) changes proportionally. B. A plot of the current through the channel versus the potential difference across the membrane reveals that the current is linearly related to the voltage; in other words, the channel behaves as an electrical resistor that follows Ohm's law (i = V/R or i = γ V). (Data courtesy of Olaf Anderson and Lyndon Providence.) C. Proposed structure of the gramicidin A channel. A functional channel is formed by end-to-end dimerization of two gramicidin peptides. (From Sawyer et al )

6 V-I Relationship of the Ion Channels In many ion channels the relation between current flow through the open channel and membrane voltage is linear but some channels don t show linear response. Rectifying channels is said to rectify, in the sense that it tends to conduct ions more readily in one direction (here positive current) than in the other.

7 Opening and Closing of Ion Channels Three physical models for the opening and closing of ion channels. A: localized conformational change occurs in one region of the channel. B: Generalized structural change occurs along the length of the channel. C: Blocking particle swings into and out of the channel mouth.

8 Stimulus Dependent Opening of Channels Several types of stimuli control the opening and closing of ion channels.

9 Three mechanisms by which voltage-gated channels become closed and nonactivatable Channels can enter into the refractory periods by different mechanisms Voltage gated channels Voltage-gated channels can enter a refractory state after activation. This process is termed inactivation. Ligand-gated channels can enter the refractory state when their exposure to the ligand is prolonged. This process, called desensitization

10 Effect of Exogenous Ligands Binding of the exogenous ligands can affect opening and closing of channels Weak and reversible, as in the blockade of the nicotinic ACh-gated channel in skeletal muscle by curare, a South American arrow poison. It can be strong and irreversible, as in the blockade of the same channel by the snake venom α-bungarotoxin. Binding of the drug valium to a regulatory site on GABA-gated Cl - channels prolongs the opening of the channels in response to GABA. Such type of indirect effect works not only on ligand-gating, but also on gating controlled by voltage or stretch.

11 Ion Channels are Composed of Several Subunits Ion channels can be constructed as heterooligomers, homooligomers or may be formed from a single polypeptide chain organized into repeating motifs, where each motif functions as the equivalent of one subunit (right). In addition to one or more poreforming α subunits, which comprise a central core, some channels contain auxiliary subunits (β or δ), which modulate the inherent gating characteristics of the central core.

12 Different Families of Ion Channels Based on Subunit. A. Certain ligand-gated channels, including the nicotinic acetylcholine (ACh) receptor-channel, have five subunits, and each subunit consists of four transmembrane regions (M1-M4). Each cylinder represents a single transmembrane α- helix. A three-dimensional model of the channel is shown on the right. B. The gap-junction channel, found at electrical synapses, is formed from a pair of hemichannels. Each hemichannel is made of six subunits, each with four transmembrane regions. A three-dimensional model of the two apposite hemichannels is illustrated on the right. C. The voltage-gated Na + channel is formed from a single (α) polypeptide chain that contains four homologous domains or repeats (motifs I-IV), each with six α-helical membrane-spanning regions (S1 to S6) and one P region thought to line the pore. The figure at the right shows a hypothetical model of the channel.