Revision 5: Effects of Electrical Signals - Ligand Gated Channels

Question 1

Ca²⁺ channel diversity

Answer 1

VGCa²⁺CPs and VGNa⁺CPs are structurally similar

-ie 1 peptide, 4 homologous repeats, 6 transmembrane domains in each with 1 being voltage sensitive, function requires 1 subunit

however Ca²⁺ channels have structural diversity, therefore blocking one VGCP does not necessarily block another

Different VGCa²⁺CPs have different primary locations, so selectively blocking one can have a localised effect

Question 2

Ca²⁺ role in synapse

Answer 2

binds to synaptotagmin, leads to formation of snare complex and ACh release

The ACh then binds to the post synaptic nicotinic ACh receptor to produce an end plate potential, the depolarisation produced is greater than the threshold so an AP is produced

Question 3

Nicotinic receptor blocker types

Answer 3

Competitive: bind at molecular recognition site for ACh, eg Tubocurarine

Depolarising: cause a maintained depolarisation at post synaptic membrane, Adjacent Na⁺ channels are not activated due to accommodation, eg succinylcholine, used in operations to induce paralysis

Question 4

myasthenia gravis

Answer 4

AImm disease that targets NAChRs

-loss of NAChRs, widened synaptic cleft, loss of folds on post synaptic membrane

Symptoms: drooping eyelids, double vision, profound weakness (inc. w/ exercise)

Treatment: AChsterase inhibitors

Question 5

Importance of intracellular Ca²⁺ control

Answer 5

many cellular processes are Ca²⁺ sensitive (due to protein in/activation)

eg fertilisation, metabolism, contraction, memory and learning, secretion, neurotransmission, apoptosis, necrosis

Question 6

Control of intracellular Ca²⁺ stores

Answer 6

1 Relative impermeability of PM to Ca²⁺

2 Ability to expel Ca²⁺ across PM using:

a) Ca²⁺-ATPase: high affinity & low capacity, Ca²⁺ binds to calmodulin, a binding trigger protein, this complex then binds to Ca²⁺-ATPase leading to Ca²⁺ removal
b) NCX: low affinity & high capacity, exchange of 1 Ca²⁺ for 3 Na⁺, electrogenic as it works best at the resting membrane potential, can lead to necrosis if ATP levels are low (see MoD)

3 Ca²⁺ buffers: limit diffusion of Ca²⁺ across cell, depends on conc. and saturation levels of binding molecules eg parvalbumin, calsequestrin, calbindin, calreticulin

4 Intracellular Ca²⁺ stores:

a) rapidly releasable stores: (sarco)ER, set up by SERCA, Ca²⁺ is moved in by enegry from ATP hydrolysis and binds to proteins eg salquestrin
b) non rapidly releasable stores: mitochondria take up Ca²⁺ to aid in buffering, regulate signalling and stim. of ATP production - they do this via a Ca²⁺ uniporter driven using respiration

Question 7

elevation of intracellular Ca²⁺

Answer 7

1 Ca2+ influx across PM (ie. altered permeability):

a) VGCa²⁺CPs: influx of Ca²⁺ down conc. grad.s
b) ROCa²⁺Cs: ligand/agonist binds to channel-opening it and allowing Ca²⁺ to enter down conc. grad.

2 Ca²⁺ release from rapidly-releasable stores - (Sarco)ER:

a) GPCRs: ligand binds to GPCR on PM -> activates G-alpa-q subunit -> binds to the phospholipid PIP₂ -> releases IP₃ (also DAG) -> binds to receptor on (sarco)ER -> release of Ca²⁺ down conc. grad.
b) CICR (Calcium induced calcium release): calcuim binds to ryanodine receptors on side of (sarco)ER -> release of calcuim down conc. grad.
- this is important in cardiac myocytes for an explosive release of large amounts of calcium

3 Calcium release from non rapidly releaseable stores from mitochondria:

-participate in normal intracellular calcium signalling w/ microdomains (areas of cytoplasm w/ large amounts of calcium due to proximity to a channel

Question 8

how is intracellular calcium returned to normal levels?

Answer 8

termination of signal, calcium removal, calcium store refilling

-the latter is done by recycling of cytosolic calcium (eg cardiac myocytes) and using calcium in mitochondria thorugh SOCs (store-operated calcium channels)