Ion Channels Flashcards
What are ion channels used for?
-Mediate the generation, conduction and transmission of electrical signals in nervous system
- Control release of neurotransmitters and hormones
-Initiate muscle contraction
-Transfer small molecules between cells (gap junctions)
-Mediate fluid transport in secretory cells
-Control motility of cells
-Provide selective permeability properties which are NB for various organelles
Ion channels
Transmemebrane protein assemblies that regulate the flow of ions across biological barriers
Membrane potential
Electrical gradients across cellular barriers that result from differences in ion concentrations on the inside and outside created by selective movement of ions across the cellular barrier
Ligand-Gated channels
The binding of a ligand to a receptor results in a conformational change that opens the ion channel
Example of activation of ligand channels
- Nicotine is an agonist of nAChR, which activates reward system of brain
-smoking-cessation medication Chantix is a partial agonist of nAChR and provides a lower level of channel binding activity upon binding than nicotine.
-The partial response can be regulated by concentration of drug
-Chantix competes with Nicotine for binding to nAChR
-It has been successful in decreasing cravings and pleasurable effects of nicotine
Example of blocking ligand channels
Functional antagonists
Compete for the natural ligands binding site but it does not cause conformational change and prevents the opening of the channel
Bind to allosteric site and either stabilize closed form of channel or cause conformational changes that prevent binding of natural ligand
-Example: alpha-neurotoxins from snake venom tightly bind to nAChR in skeletal muscle which prevents acetylcholine-mediated neurotransmission (through the opening of nAChR) causing paralysis in the snake bite victims
Voltage-gated channel
-Have no natural ligand
-Open and close as a result of changes in membrane potential produced as electrical currents that move through biological systems
-Used for propagation of nerve impulses through axons, muscle contractions and cardiac function
Activating voltage-gated channels
- Stimulus above threshold leads to rapid channel opening
- Depolarization caused by ion flow through channel, hyperpolarisation then causes closing of inactivation gate
- The inactivation gate remains closed until membrane potential is rest by action of opposing forces
- Stimulation of the channel will not evoke a response until the refractory period has ended and the resting potential of -70mV is restored
Modulation of activity of voltage-gated channels
-Not possible with agonists and antagonists
-must block the open channel directly
-Alternatively, compounds can interact with the gates at sites other than the pore region, which is allosteric modulation as the active site of ion channels is the pore through which ions move
Drugs that block voltage-gated channels
-Flecainide blocks Nav1.5, a voltage-gated sodium channel that plays a major role in cardiac function. It is used in the treatment of arrhythmia and prevention of tachycardia
-Margatoxin is a type of scorpion venom that block Kv1.3 channels which is a voltage-gated potassium channel found in various cell types including neurons. Blocking Kv1.3 can induce immunosuppression by decreasing T-cell proliferation
Drugs that allostericly open voltage-gated channels
Retigabine is an anticonvulsant that treats epilepsy and seizures
It stabilizes the open forms of voltage-gated potassium channels Kv7.2 and Kv7.3 leading to increased potassium flow and seizure suppression.
Other gating mechanisms
-temperature-gated channels
-mechanosensitive ion channels
-pH gating
-Phosphorylation
-GPCR mediated
Ion channel openers
Diazoxide
-vasodilator used for hypertension, smooth muscle relaxing activity
Ion channel closers
Amiodarone
- Used to treat cardiac arrhythmias, prolonging the repolarisation
