Ion channels and ionotropic receptors

Question 1

ion channels vs ionotropic receptors

Answer 1

ion channels are voltage triggered
iontropic receptors are triggered by ligand binding

Question 2

Why are ion channels important in the membrane?

Answer 2

They allow ions to flow in and out the cell by reducing the resistance from 10^8 Ω to 10^3Ω which is important for synapse communication and muscle contraction.

Question 3

How does the membrane contribute to effective communication?

Answer 3

• acts as a capacitor: allows compartmentalisation of electrolyte media of opposite charges, differential distribution of ions where there are more Ca2+ Na+ and Cl- in the extracellular space while K+ is greater in the intracellular space.
• acts as an insulator: not permeable to ions

Question 4

What is the organisation in the skeletal muscles?

Answer 4

• Skeletal muscles made up of muscle fibers (cell).
• muscle fibers contain muscle fibrils (myofibrils)
• myofibrils are sectioned into sacromeres
• within each sacromere, there are actin (thin filaments) and myosin (thick filaments)

Question 5

How does muscle contract?

Answer 5

• in the presence of Ca2+, (sliding filament model:) actin and myosin heads form cross bridges leading to a power stroke, causing muscle contraction

Question 6

How do muscles relax after performing a power stroke?

Answer 6

• after power stroke, ADP + P are released from myosin heads
• ATP binds to myosin heads to detach from actin (cross bridge breaker)

Question 7

Function of topomyosin and troponin?

How are they overcomed?

Answer 7

• ## they bind onto actin to prevent myosin heads from attaching to actin

• Ca2+ binds to troponin, changing the conformation of tropomyosin which alows myosin heads to bind to actin

Question 8

What is the effect of calcium on cardiac muscles?

start from the sacrolemma and ion channels

Answer 8

• sacrolemma have T-tubules lined with DHP receptors
• an action potential causes L-type channel to open, influx of Ca²⁺
• this stimulates SR to release Ca²⁺ stores
• Ca²⁺ binds to TN-C, free actin for myosin head to bind

DHPR: dihydropyridine receptor (L-type calcium channel)
TN-C: troponin-C

Question 9

what is the effect of calcium on smooth muscles?

start with L-type channels

Answer 9

MC
- L-type Ca²⁺ channels open, influx of Ca²⁺
- Ca²⁺ stores released from SR
- formation of Ca²⁺-CM activates MLCK
- MLCK phosphorylates MLC in the presence of ATP for MC so it can bind to actin
- Gi-R decreases cAMP (inhibition of adenylyl cyclase activity)
- Gq-R increases IP3 (stimulates Ca²⁺ release from SR) and rho-kinase (inactivates MLCP)
MR
- NO increases cGMP which activates MLCP (dephosphorylates MLC)
- Gs-R increases cAMP -> more PKA which inhibits MLCK

MLCK/P: myosin light chain kinase/phosphatase
MLC: found on the myosin heads
MC: musce contraction
MR: muscle relaxation
CM: calmodulin
cGMP: Ca²⁺ sequestration into SR
cAMP: PKA binds competitvely to MLCK to prevent Ca²⁺ -CM from activating it

Question 10

Give 2 examples of ionotropic receptors

Answer 10

-GABAA-R (located at post-synapse)
-ACh-R

-they are found in neurons
-R: receptor

Question 11

What is the structure of GABAA-R?

Answer 11

5 distinct sites (GABA site, Benzodiazepine site, Steroid site, Barbituate site, Picrotoxin site) and a Cl⁻ channel

Question 12

What is the function of GABAA-R?

Answer 12

• ## it promotes the influx of Cl⁻ through its Cl⁻ channel

Question 13

How is GABAA-R regulated by different drugs?

Answer 13

• Isoguavacine: selective agonist (increase influx of Cl⁻)
• Bicuculline: selective antagonist (competes with GABA to bind to GABA site)
• Benzodiazapine: agonist ( increases freq of Cl⁻ channel opening)
• barbituate (phenolbarbital): agonist ( increases freq/duration of Cl⁻ channel opening)

Question 14

How is ACh receptor regulated by different chemicals?

Answer 14

• Nicotine: selective agonist (act at muscarinic R and NMJ) -> muscle contraction by depolarisation (>NA+ influx and <K+ efflux) but prolonged exposure can lead to R desensitization
• α-bungarotoxin (snake venom): non-depolarising seective antagonist at NMJ -> paralysis

Question 15

How does defective ion channel function lead to cystic fibrosis?

Answer 15

• Genetic mutation in epithelial CL channel (CFTR), deletion of Phe at position 508
• prevents CFTR from reaching the surface membrane
• impairs Cl⁻ conductance (remains outside cells) -> dehydration in airway epethelia -> thicker mucus -> bacterial growth -> lung infections

CFTR: Cystic Fibrosis Transmembrane Conductance Regulator, chloride ion channel

Question 16

How does defective ion channel function lead to Long QT syndrome?

Answer 16

• it is a heart rhythm disorder (rapid and chaotic HR)
• loss-of-function mutation in cardiac K+ channels (slow to open) decreases K+ current -> slower repolarisation
• long QT interval in electrocardiogram

Question 17

Discuss the structural differences between LGIC and VGIC.

Answer 17

LG vs VG
- Activation by binding of specific ligand to LBS on LGIC vs Activation converting a chemical or mechanical signal into an electrical signals that change membrane potential in excitable cells (neuron and msucle cells)
- Made up of 5subunits, receptor binding site at extracellular site vs transmembrane: votaltage-sensing domain, pore domain, intracellular ligand binding site
- Both are selective for specific ions

LBD: ligand binding domain

Question 18

what is the location of the LG vs VG in the body?

give examples

Answer 18

LGIC is found at the synapse (ACh receptor, GABA Cl- receptor) vs VGIC found throughout excitable cells (neurons, muscles)

Question 19

LGIC vs VGIC in terms of drug modulation

Answer 19

LGIC are targeted by drugs that mimick/ block neurotransmitters (benzodiazepines, phenobarbital) vs VGIC targeted by channel blockers (Ca2+ channel blockers - verapamil, amlodipine