NMJ's and Calcium Flashcards
What happens at the nerve terminal when an action potential arrives?
Ion channels in the nerve terminal:
- voltage-gated Na+ channels
- voltage-gated K+ channels
- voltage-gated Ca2+ channels
depolarisation opens voltage-gated Ca2+ channels. Ca2+ entry causes release of neurotransmitter. Because the concentration of Ca2+ inside is so low, the Ca2+ influx through Ca2+ channels can raise the internal concentration of Ca2+ significantly.
Where are L-type calcium channels present?
L-type calcium channel present in heart, lungs, skeletal muscle.
What is the role of mitochondria in the postsynaptic cleft?
-Calcium storage to reduce calcium concentration intracellularly after action potential arrives
Describe the mechanism of transmitter release
- Ca2+ entry through Ca2+ channels
- Ca2+ binds to synaptotagmin
- Vesicle brought close to membrane
- Snare complex make a fusion pore
- Transmitter released through this pore
How does a neuromuscular blocker work?
Competitive blocker combines with nicotinic receptors and blocks the channel from opening (acetylcholine can’t bind to its binding site)
Depolarising blocker can itself open the nicotinic acetylcholine channels and as they remain open, inactivation of sodium ion channels due to continuous depolarisation.
What is a miniature endplate potential?
- absence of calcium entry
- around 1mv amplitude, not threshold
- spontaneous response to single vesicle of acetylcholine
Describe the condition of myasthenia gravis
- Patients suffer profound weakness
- Weakness increases with exercise
- Caused by antibodies directed against nAChR on postsynaptic membrane of skeletal muscle
- Antibodies lead to loss of functional nAChR by complement mediated lysis and receptor degradation
- Endplate potentials are reduced in amplitude leading to muscle weakness and fatigue
What are the advantages and disadvantages of the large inward gradient for calcium?
Advantages:
- changes in [Ca2+] occur rapidly with little movement of calcium
- little has to be removed to re-establish resting conditions
Disadvantages:
- energy expensive
- inability to deal with Ca2+ easily leads to Ca2+ overload (loss of regulation and cell death)
What is calcium used for in the body?
It is responsible for or regulates: fertilization, proliferation, secretion, neurotransmission, metabolism, contraction, learning and memory, apoptosis and necrosis
How is the calcium gradient set up and maintained?
- Relative impermeability of plasma membrane. Membrane permeability regulated by open/close state of ion channels
- Expulsion of Ca2+ across the plasma membrane via Ca2+-ATPase pump and Na+/Ca2+ exchanger
- Calcium buffers
- Calcium stores
What are trigger proteins?
- Some proteins bind Ca2+
- alters function
- trigger proteins calmodulin, troponin– e.g. synaptotagmin
- Distinct from Ca2+ buffers that have the role of regulating the free [Ca2+]
How is calcium elevated and returned to basal levels?
- Ca2+ influx across the plasma membrane ie. altered membrane permeability:
a) Voltage-operated Ca2+ channels (VOCC). Different types of Ca2+ channels with different regulatory features - L, N, R, P/Q, T-types. Driving force = concentration gradient.
b) Inotropic receptors. Driving force = concentration gradient/electrical gradient. They are ligand-gated: eg. NMDA/AMPA receptors for glutamate; some nicotinic (acetylcholine) receptors - Ca2+ release from rapidly releasable intracellular stores – the sarco/endoplasmic reticulum. (SERCA moves calcium in, Ca2+ binding protein inside e.g. calsequestrin–low affinity, high capacity ).
How is release of calcium from intracellular stores mediated?
a) G-Protein coupled receptors (e.g metatrobic glutamate receptor)
- arrival of stimulus
- alpha q subunit activates phospholipase C which cleaves PIP2, into DAG and IP3
- IP3 binds to ligand gated receptor on ER membrane causing pore to open and Ca2+ to be released
b) Ca2+ induced calcium release (CICR)
Calcium regulates the opening of ligand gated receptors in ER membrane
Describe the importance of RyR
- Calcium binds to ryanodine receptor to trigger change in conformation and pore opening to release calcium.
- Conformational coupling with VOCC (depolarisation changes shape of VOCC which changes shape of RyR which causes calcium release). This mechanism important in cardiac myocytes when sodium entry from T-tubule depolarises cell, causing calcium release from SER via RyR and allows contraction.
Describe the importance of uptake and release of calcium from mitochondria
mitochondrial uptake when [Ca2+] is high protective BUT….. participate in ‘normal’ Ca2+ signalling due to microdomains
-role in cell death – eg. apoptosis
mitochondrial calcium overload/dysfunction key for triggering cell death in eg. ischemic and traumatic brain injury, Alzheimer’s, Parkinson’s, Huntington’s and amyotrophic lateral sclerosis
