Lecture 4 - Ion channels Flashcards
Describe the pathway from stimulus to effector
stimulus –> receptor –> control centre –> effector
What is an ion channel?
A channel is a transmembrane protein that transports molecules from one side of the membrane to the other. They are specific - Na+, K+ or Cl- ions, open or gated.
Name 3 types of channels
- Open/leakage channels
- Voltage gated channels
- Ligand gated channels
What are 3 essential functions of ion channels?
- Transport ions across membrane (e.g. secretion/absorption of fluids)
- Regulate membrane potentials (e.g. nerve & muscle cells for high-speed communication)
- Ca2+ influx into the cytoplasm (e.g. secretion & muscle contraction)
What is an alpha helices?
a right hand-helix conformation
What are subunits?
Single protein that forms with others to form protein complex
What is a transmembrane domain (TM)?
protein that spans the width of the membrane from the extracellular to intracellular sides usually a helical shape
What is a P-loop or pore?
Pocket where ion will bind
Describe the main structural features of all ion channels
- Transmembrane proteins made up of 2+ a-helices that cross the lipid bilayer
- Made up of 2-6 subunits which usually surround the ‘pore’
Ion channels are classified into subgroups based on:
- gating mechanisms
- ion selectively of the pore (defined by physical size of ‘filter’ and amino acids lining the pore)
Describe the evolution of ion channels
- 400 genes in humans code for membrane channels, knowledge of structure reveals evolutionary relationships
- the pH-regulated K+ channel KcsA from the bacterium Streptomyces lividans serves as a model for all channels
Describe the structures of simple ion (K+) channels
- TM helicase structures form a p-loop (pore) - highly selective (size & charge)
- on cytoplasmic side, TMs are more tightly packed creating a ‘gate’.
Membrane potential, mechanical stress and ligand control the gate.
What are the 2 main functions of voltage-gated ion channels?
- Na+ & K+ create action potentials in excitable cells
- Ca2+ transported into cytoplasm where 2nd messenger elicits a cellular response
How are voltage-gated ion channels different from simple ion channels?
- additional helices S1 and S4 form a separate ‘voltage-sensing domain’ lateral to the subunits
- large polypeptides that extend into the cytoplasm
- plugging mechanism
What are transient receptor potential (TRP) channels?
Share common structural features with voltage-gated channels, but evolved to sense chemicals and physical stimuli. Special receptors that only open in extreme temperatures (emergency response)
Describe the structure of ligand-gated ion channels
Similar in structure to voltage-gated but controlled by the binding of a ligand - e.g. cyclic nucleotide-binding domain, Calmodulin bound to N-terminal
What are gated channels controlled by?
intracellular or extracellular ligands
What do Na+/K+ selective channels control?
membrane excitability - depolarise cells
What do channels with added permeability to calcium do?
directly regulate activity of calcium sensitive proteins
What do Cl- selective channels control?
control membrane excitability - reduce resistance/hyperpolarise cells, reduce action potential firing
Describe the make up of a cys-loop type receptor with pentametric assembly - e.g. nicotinic acetylcholine receptor (nAchR)
In muscle composed of 5 subunits. Each has 4 TM’s (M1,M2,M3,M4) with large external facing N domain and intracellular loop between M3 and M4. M2 lines the pore.
Explain how multiple subunits exist within any one ligand-gated ion channel family
- different subunit combinations make up receptors in different parts of the brain
- complexity provides diversity and opportunity for drug targeting
- e.g. nAcha4 is involved in reward pathways and nicotine addiction
Explain how nicotinic receptors can be targeted for nicotine addiction
- Neuronal nAchRs - a2-10 & B2-4 - each has different affinity (depending on composition and location)
- a4B2 are expressed in cortex & hippocampus and have high affinity to agonists nicotine and vareniciline
- chronic exposure leads to receptor upregulation
- genetic studies shown specific polymorphisms in subunit genes (CHRNA4 - a4) and (CHRNA6 - a6) are linked to tobacco dependence
- Rare variants have been shown to be protective against nicotine dependence
How does a mutation in mAchR cause autosomal dominant nocturnal frontal lobe epilepsy?
- Mutations in the M2 region of the human a4 neuronal nicotinic subunit causes ADNFLE - 9 mutations have been identified to date
- use-dependent potentiation and delay in rising phase caused by a slow unblocked of closed receptors
- enhanced receptor function = increased nicotinic-mediated transmitter released = ADNFLE seizures
Describe features of glutamate receptors - tetrameric assembly
- glutamate is main neurotrasmitter in the brain
- tetramer with similar structure to KcssA except pore is inverted
- forms as dimer of dimers. ligand binding site is in a cleft that ‘closes’ when occupied
- vital to every aspect of brain function and dysfunction contributes to human diseases
