CaV channels Flashcards
what do CaV regulate
intracellular calcium concnetration and contribute to calcium signalling
what do CaV mediate
calcium entry into cells in response to depolarisation
what do CaV control
- AP generation and conduction
- sensory processes
- muscle contraction
- secretion of transmitters and hormones
- cell differentiation and gene expression
what is the opening of CaV channels modulated by
hormones, transmitters, protein kinases and phosphatases
what are CaV targets for
toxins and drugs
what is spontaneous mutations of CaV channel subunits associated with
hyperexcitable disorders
what is the trigger for fast evoked transmitter release
calcium influx
what is the typical calcium concentrations at rest
extracellularly 1-2mM
intracellularly <0.1mM
what is required for transmitter release
an elevation in intracellular calcium concentration
what is the primary structure of the CaV subunit
4 repeat domains, each with 6 transmembrane segments and a membrane-associated loop between S5 and S6
what are present in the P regions of each domain that are important for determining selectivity for calcium ions
glutamic acid residues (E)
what do high-voltage activation calcium channels require
large depolarisation (to -20mV)
what do low-voltage activation calcium channels require
much more negative potentials (-60mV)
what do HVA calcium channels display
variable inactivation
what do LVA channels display
rapid voltage dependant inactivation
as HVA channels are long-lasting, they are also called
L-type calcium channels
as LVA channels display fast voltage-dependant inactivation, they are termed as
transient, or T-type calcium channels
what are N-type channels
neuronal (HVA)
what are P-type channels
purkinje cells (HVA)
what are Q-type channels
found in cerebellar granule neurones (HVA)
what are R type channels
so-called resistant component of neuronal channels (L/HVA)
where are the different channel types found
L and T are found in a wide range of cells
N, P, Q and R are typically found in neurones
what blocks L type channels
DHPs
what is the function of L type channels
E-C coupling
hormone secretion
muscle contraction
what blocks N type channels
conotoxin and GVIA
what is the function of N type channels
neurotransmitter release
what blocks P type channels
agatoxin and IVA
what is the function of P type channels
neurotransmitter release
what blocks Q type channels
conotoxin and MVCII
what is the function of Q type channels
neurotransmitter release
what blocks R type channels
tarantula toxin
what is the function of R type channels
Ca APs
neurotransmitter release
what blocks T type channels
mibefradil
what is the function of T type channels
repetitive firing
how many auxhillary subunits do CaV channels arise from
5
how many individual genes does the alpha subunit have
10
how many beta subunits are there and where are they located
4 - intracellulary
how is the alpha 2 subunit attached to the membrane
through disulphide linkeage to a delta subunit, which anchors the alpha 1 subunit via a single transmembrane segment
what does the alpha2delta subunit occur as
4 seperate genes
what is the gamma subunit comprised of
a glycoproein with 4 transmembrane segments - and up to 8 genes
how many subunits do L type channels have
all 5
L type channels - location and channel type
CaV1.1-1.4 - cardiac and skeletal muscle, neurones and endocrine cells
P/Q type channels - location and channel type
CaV 2.1 - nerve terminals, dendrites
N type channels - location and channel type
CaV2.2 - nerve terminals, dendrites
R type channels - location and channel type
CaV2.3 - cell bodies, nerve terminals and dendrites
T type channels - location and channel type
CaV 3.1-3.3 - cardiac and smooth muscle, neurones
what do L-type CaV channels displau
multiple gating kinetics
what regulates the CaV1 family
phosphorylation
what are L-type CaV channels modulated by
hormones and neurotransmitters in muscle and neurones
what do B-adrenergic agonists increase
cardiac AP amplitude, muscle contractility and rate
what does adrenergic stimulation do
increase probability of opening and the number of functional CaV channels
any process that causes increase in cAMP levels induces this effect
what does presence of a B-sunubit do
considerably enhance b-adrenergic agonist activation of CaV1.2
where does PKA phosphorylate native b subunits
cardiac tissue
what is the CaV2 family regulated by
G-proteins
what do GPCRs couple to
CaV channels - N, P/Q
what does g-protein coupling do
inhibits calcium current - local membrane action
what are g-proteins responsible for
a decrease in synaptic transmission as calcium entry at nerve terminal is reduced
what does a depolarizing prepulse within GPCRs do
reduces/abolishes the inhibitory effect
what regulates CaV channel activity
integration of multiple signalling pathways
what happens when CaV1.1 is missing/non-functional
die at birth of asphyxiation
what happens when CaV1.2 is missing/non-functional
die before birth as unable to contract cardiac muscle
what happens when CaV1.3 is missing/non-functional
deaf, cardiac arrhythmias
what happens when CaV1.4 is missing/non-functional
blind
what happens when CaV2.1 is missing/non-functional
severly ataxic, absence seizures
what happens when CaV2.2 is missing/non-functional
hyposensitivity to pain
what happens when CaV2.3 is missing/non-functional
hyposensitivity to pain
what happens when CaV3.1 is missing/non-functional
resistant to baclofen-induced seizures
what happens when CaV3.2 is missing/non-functional
resistant to baclofen-induced seizures
what happens when CaV3.3 is missing/non-functional
compromised vascular function
the major classes of drugs that act on L-type CaV channels are:
- DHPs
-phenylalkylamines
-benzothiazepines
what are drugs that act on L-type CaV channels used to treat
hypertension, cardiac arrhythmias and ischaemic heart disease
how do the drugs that work on L-type CaV channels work
act to block Ca2+ influx and they do so by more than 1 mechanisms, drugs may bind to the same site but have converse effects
what do dihydropyridines act as
allosteric modulators, in that they alter the gating behaviours of L-type CaV channels
where do DHPs bind
specific sites associated with the S5 and S6 segments of the alpha subunit
how do phenylalkylamines work
they block L-type Ca2+ channels in a use-dependant manner from the intracellular side of the membrane
where do PAAs bind
inner end of the transmembrane pore
where do benzothiapines bind/work
bind to residues in S5-S6 linker of domain IV, act extracellularlu
where are N, P/Q and R types exclusively associated with
the peripheral NS
where are T type channels exclusively associated with
cardiovascular and neuronal tissues
what is ziconotide and what does it do
a peptide toxin that interacts with N-type calcium channels
what is gabapentin and what does it do
originally synthesised as GABA - mimetics (for treatment of epilepsy) - used to treat chronic pain through their interaction at the alpha2delta subunit (supresses pain)
what is hypokalemic periodic paralysis (type 1)
CaV1.1 expressed specifically in skeletal muscle: mutations (S4 regions) result in reduced calcium current and muscle weakness
what is timothy syndrome
a rare childhood multi-organ disorder - cardiac defects, immune deficiency, cognitive abnormalities etc.
generally sporadic
due to mutations in CaV1.2, causing lack of channel inactivayion and so enchanced calcium entry leading to severe cardiac dysregulation
what is night blindness
multiple mutations (>60) associated with loss of CaV1.4
cause by decreased transmitter released from retinal photoreceptor terminals
what are migraines
a rare hereditary disorder resulting in transient migraine attacks
associated with mutations of CaV2.1 causing increased channel activity and transmitter release
what is ataxia
patients have recurrent attacks of motor dysfuncion
associated with disruption of CaV2.1 gene, preventing formation of normal functional channels and so loss of calcium current
what is epilepsy
mutations in CaV auxhillary subunits (alter P/Q function)
