Voltage-Gated Calcium Channels Flashcards
(27 cards)
Cav structure
- alpha very similar to that of Navs
- 4 accessory subunits
- 4 VSDs around central pore domain
- lateral fenestrations
- EC turret loop domain important for binding toxins and some drugs
- 2 pore helices P1 and P2
- VSDs similar to Navs and Kvs
Cav VSDs
- similar to Navs and Kvs
- stabilised by negative charged residues in neighbouring helices
- the R/K in S4
Cav selectivity
- 4 Glu
- 3 calcium binding sites within the selectivity filter
L-type Cavs - Cav1.1
- skeletal muscle
- Cav1.1 physically interacts with RyR
- to promote calcium release from the SR
L-type Cavs - Cav1.2
- cardiac muscle
- no physical contact between Cav1.2 and RyR
- relies on calcium-induced calcium release
- excitation-contraction coupling
Regulation of L-type Cavs - CDI
calcium-dependent inactivation
- mediated by CaM
- tethered to IQ motif of C terminal of L-type Cavs
- CaM fails to associate when IQ is mutated = no CDI
Regulation of Cav1.2 - phosphorylation
regulation by PKA
- stimulation of beta-adrenergic receptors = increased calcium current
- increased force of contraction (positive ionotropic effect)
- due to shift to high Po
phosphorylation of rad associated protein
- alters association with auxiliary subunits
- relieves inhibition of Cav1.2
Pathophysiology of L-type Cavs
- hypokalaemic periodic paralysis
- malignant hyperthermia
- Timothy syndrome
Hypokalaemic period paralysis
- rare, autosomal dominant
- inherited neuromuscular disorder
- muscle weakness and paralysis
- matching decreased serum [K]
- missense mutations in Cav1.1
- mutations in VS S4 causes abnormal gating pore omega current
- altered membrane excitability
Malignant hyperthermia
- main cause of death by anaesthesia
- massive increase in cytosolic [Ca] in skeletal muscle
- causes vigorous contraction
- can cause a potentially fatal increase in body temperature
- in susceptible individuals, mutations are generally in RyR1
- minor cases due to Cav1.1-alpha mutations
Timothy syndrome
- autosomal dominant
- gain of function mutations in S6 domain of alpha-1C subunit of Cav1.2
- longer current, slower inactivation and increased Po
- enhanced calcium influx and delayed cardiomycocyte repolarisation
- increased risk of severe ventricular arrhythmia
Drugs against L-type Cavs
- verapamil
- nifedipine
- diltiazem
- dihydropyridines
- phenylalkylamines
- tetrandrine
Verapamil, nifedipine and diltiazem
- L-type Cav blockers
- for hypertension, angina and arrhythmias
verapamil and diltiazem
- more cardioselective
- class IV anti-arrhythmics
- use-dependent against Cav1.2
diltiazem
- binds deeper than DHPs
- via lateral fenestration (DIII and DIV)
Dihydropyridines
- anti-hypertensives
- more vasoselective
- decrease peripheral resistance
- long acting or extended release for angina
bind external, lipid-facing surface positioned at interface of domains III and IV
- allosteric inhibition
- induces asymmetry within selectivity filter
- partially hydrated calcium then interacts with subunit and blocks pore
Phenylalkylamines
bind in central cavity of pore beneath selectivity filter
Tetrandine
- plant-based
- traditional Chinese remedy for autoimmune disorders, cardiovascular disease and hypertension
- blocks central inner pore of Cav1.2 directly
Cav2 subfamily
- variable calcium current through alternate splicing
- in synaptic terminal for neurotransmitter release
- Cav2.1 and 2.2 contain a synaptic protein interaction (synprint) site that binds SNAREs
- clustering of channels at the active site
- some physically interact with BKCa and provide calcium needed to activate them
Cav2 channelopathies
P/Q-type:
- episodic ataxia
- generalised epilepsy
N-type:
- neuropathic pain
Drugs against Cav2
ziconitide
- toxin-based therapeutic
- intrathecal
- selectively blocks Cav2.2
- for severe chronic pain in patients unresponsive to opioids
- low therapeutic index
Z160
- small molecule therapeutic
- trialled for chronic pain
- selective for Cav2.2
- use-dependent
- alternative to ziconitide
- trials failed to show efficacy
gabapentanoids
- e.g. gabapentin
- AED
- acts on alpha-2-delta
- decrease trafficking to the membrane
- decrease calcium current
Beta subunits
- alpha can function alone but low expression and abnormal current
- corrected by beta
- helps alpha evade uniquitination and proteasomal degradation
- mutations in AID region of alpha prevents interaction with beta so decreases calcium current
Alpha-2-delta subunits
- membrane anchored via glycosylphosphatidylinositol linker
- von Willebrand factor A domain for protein-protein interactions
- promote trafficking to the membrane
- interaction with thrombospondins promotes synaptogenesis
- mutations implicated in neuropathic pain, epilepsy and arrhythmias
T-type subfamily
- T-type = Cav3
- at RMP, some Cav3s remain open to create the window current
- so some calcium influx when membrane isn’t depolarised
- T-type current important in SAN for pacemaker potential
T-type in the brain
- thalamus and amygdala
- 2 patterns of AP firing
- tonic firing when depolarised
- when membrane is <-70mV, same depolarising stimulus causes high frequency bursts of APs
- low threshold calcium spikes important for sleep and arousal
- may be implicated in epilepsy
T-type deinactivation
- at Vrest, Cav3s remain tonically inactivated
- transient hyperpolarisation allows them to recover from inactivation
- calcium current mediates fast depolarisation for Nav opening = AP bursts
