6 - Neuronal Ca Channels Flashcards
Five roles of Ca++ channels in excitable cells
- Intracellular signals
- Ca++ - dependent enzymes
- Gene regulation
- Transmitter release
- Electrical behaviour
- effects of Ca++ as charge carrier (intracellular messenger)
- Effects of Ca++ on other membrane ion channels
- Neurite outgrowth
- Muscle contraction
In the nerve fibre, the AP has only ____ and ____ components. How is this different from the nerve cell body, nerve terminal and muscle cell?
In the nerve fibre, the AP has only Na+ and K+ components.
The nerve cell body, nerve terminal and muscle cell, AP also has Ca++ component
Enzymes such as _____ and _____ are activated by Ca++ (intracellular messenger)
Enzymes such as protien kinases and proteases are activated by Ca++ (intracellular messenger)
Transmitter release is triggered by:
High [Ca++]
Why keep intracellular [Ca++] so low (<<100nM vs 2mM extracellular)
(4)
- Maintain sensitivity
- keep noise ⤓ , signal ⤒
- Speed
- Big gradient
- fast, large, local increase in Ca++
- Selectivity
- activates only local processes, domain collapses rapidly
- Safety
- Ca++-sensitive processes only affected within domain
- sensitivity can be low
- prevents spurious activation by ambient Ca++
- sensitivity can be low
- Ca++-sensitive processes only affected within domain
What is the importance of local [Ca++] in Ca++ domains?
locally high concentration (near Ca++ source) = local actions
What is the role of Ca++ channels in excitable cells?
- in neuronal cell bodies, Ca++ enters through Ca++ channels while Na+ enters through Na+ channels during AP
- Elevated [Ca++]i activated gK,Ca’s
- BK channel (gK,Ca) repolarizes neuron during the AP
- AK channel (IAHP) reduces repetitive firing
- Involved in “bursting” behaviour
Role of Ca++ in excitable cells:
- in neuronal cell bodies, Ca++ enters through _______ while Na+ enters through ______ during AP
- Elevated [Ca++]i activates _____
- ________ repolarizes neuron during the AP
- _______ reduces repetitive firing
- Involved in “______” behaviour
- in neuronal cell bodies, Ca++ enters through Ca++ channels while Na+ enters through Na+ channels during AP
- Elevated [Ca++]i activates g<u>K,Ca's</u>
- BK channel (g<u>K,Ca</u>) repolarizes neuron during the AP
- AK channel (I<u>AHP</u>) reduces repetitive firing
- Involved in “bursting” behaviour
What are Ca++ channels classified by?
- Electrical behaviour and
- Pharmacology
HVA (high voltage activated Ca++) channels start to activate near ___________
Include: ___, ___, ___, ___, ___ channels
HVA (high voltage activated Ca++) channels start to activate near AP threshold (about -40mV)
Include: L-, N-, P-, Q-, R- channels
LVa (low voltage activated) Ca++ channels start to activate near _______
include ___ channels
LVa (low voltage activated) Ca++ channels start to activate near resting potential (-70mV)
include T channels
_____ relationships distinguish Ca++ channels
I-V relationships distinguish Ca++ channels
Which Ca++ channels have single-channel properties?
T, N, L
Where are L-type Ca++ channels found?
- Skeletal, cardiac muscle and to some extent in nerve
- Conducting myocytes on AV/NA nodes
- Lots in muscle - useful for biochemical studies (triggers Ca++ cascade rather than conduct Ca++)
L-type Ca++ channels are _______ activated
L-type Ca++ channels are high voltage activated (~-40mV)
L-type Ca++ have what role in muscles?
Act as a voltage sensor to trigger Ca++ cascadew
L-type Ca++ channels prefer to pass ___ rather than Ca++
L-type Ca++ channels prefer to pass Ba++ rather than Ca++
What are the pore-forming subunits in L-type Ca++ channels?
alpha1C and alpha1D
L-type Ca++ channels are blocked by most _______
As well as ________ and _________
L-type Ca++ channels are blocked by most dihydropyridines (nifedipine, nimodipine etc)
Hypertension
Also blocked by verapamil and inorganic blockers (Cd++, Co++, Ni++)
__________ agonists such as BAYK-8644 will open L-type Ca++ channels
dihydropyridine agonists such as BAYK-8644 will open L-type Ca++ channels
L-type Ca++ channels are insensitive to most ________ (commonly used to identify presence of other Ca++ channels)
L-type Ca++ channels are insensitive to most toxins (conotoxins, agatoxins) (commonly used to identify presence of other Ca++ channels)
What increases opening probability of L-type Ca++ channels?
- G-protein coupled agonists
- esp beta-adrenergics
- via a cAMP/protein kinase A mechanism
- phosphorylate channel = increase opening probability
- via a cAMP/protein kinase A mechanism
- esp beta-adrenergics
Where are N-type Ca++ channels most commonly found?
neurons
(not found in muscle)
Open time of N-type Ca++ channels vs L-type Ca++ channels?
N-type Ca++ channels have a shorter open time than L-type
Inactivation of N-type vs L-type Ca++ channels
N-type inactivate relatively rapidly compared to L-type
Pore of N-type Ca++ formed by _____ subunits
Pore of N-type Ca++ formed by alpha<u>1B</u> subunits
What toxins block N-type Ca++ channels?
- omega-conotoxin G-VI-A
- marine cone snail
- omega-conotoxin M-VII-C
N-type Ca++ channels are insensitive to _______, and _______ (which can block L-type Ca++ channels)
N-type Ca++ channels are insensitive to dihydropyridines, and omega-agatoxin-IV-A (spider) (which can block L-type Ca++ channels)
What decreases the opening probability of N-type Ca++ channels?
- G-protein coupled agonists
- eg opioids, alpha2-adrenergics, GABAB agonists
Mechanisms to decrease opening probability of N-type channels?
- Direct, voltage sensitive interaction of G-protein betagamma subunits with channel
- Indirect, voltage-insesntive modulation of the channel via second messengers
- PRESYNAPTIC INHIBITION
Unlike N-type and L-type Ca++ channels, T-type Ca++ channels prefer _____ over ____
Unlike N-type and L-type Ca++ channels, T-type Ca++ channels prefer Ca++ over Ba++
T-type channels are _______-activated
T-type channels are low voltage-activated (LVA)
- relatively negative voltage of activation
T-type Ca++ channels have Rapid _______
T-type Ca++ channels have Rapid Inactivation
Only open for a short time
T-type Ca++ channels require _____ to remove inactivation
T-type Ca++ channels require strong hyperpolarization to remove inactivation
T-type Ca++ channels are important in _____ of cells, not directly in transmitter release
T-type Ca++ channels are important in Burting behaviour of cells, not directly in transmitter release
T-channels are formed from _____, _____ or ____ subunits
T-channels are formed from alpha<u>1G</u>, alpha<u>1H</u> or alpha<u>1I</u> subunits
T-current bursting requires:
Opposing currents, offset in time
T-type VDCC makes bursting possible when cell is _________
T-type VDCC makes bursting possible when cell is hyperpolarized
Does not affect cell when depolarized
Slow AP caused by T-current
Which inorganic blocker is T-type VDCC most sensitive to?
Nickel (moreso than Cd2+ or Co2+)
T-type Ca++ channels are blocked by ______
T-type Ca++ channels are blocked by mibefradil
antihypertensive
_________ will block T-type VDCC at high concentrations
dihydropyridines will block T-type VDCC at high concentrations
_______ act as T-type channels
anticonvulsants act as T-type channels
- Ethosuximide metabolites
- mehtylphenylsuccinate-MPS
- Phenytoin
- ^^ block T-type channels
T-currents can be modulated by _________
T-currents can be modulated by G-protein coupled agonists
- Inhibition by Gbeta-gamma coupling
- PKC family inhibits
- Dopamine (DA), somatostatin, Angiotensin II
P/Q-type Ca++ channel nomenclature arose from _______ where they were first described
P/Q-type Ca++ channel nomenclature arose from purkinje cells (large GABAergic cells of cerebellum) where they were first described
P/Q type VDCC prefer conducting ____ over Ca++
P/Q type VDCC prefer conducting Ba++ over Ca++
____forms pore of P/Q-type Ca++ channels
alpha<u>1A</u> forms pore of P/Q-type Ca++ channels
P/Q-type VDCC’s are important in ______ of purkinje cell dendrites
P/Q-type VDCC’s are important in bursting behavior of purkinje cell dendrites
Describe A-E
A - Na+ spikes alone
B- Na+ and Ca++ spikes
C - na+ firing eventually stops in presence of Cd++
D - Oscillatory Na+ and Ca++ responses
E - full trace of response in D
P/Q-type VDCCs require _____ to deactivate
P/Q-type VDCCs require relatively strong hyperpolarization to deactivate
Inactivates rapidly
What forms the pore of R-type VDCCs
Alpha1E
R-type VDCC’s are resistant to:
Most toxins (conotoxins, agatoxins)
R-type VDCCs are modulated by ______
some agonists
VDCCs are made up of several subunits: ___, ___, ___, ___, ____
VDCCs are made up of several subunits: alpha1, alpha 2, beta, gamma, delta
____ is the pore-forming molecule in VDCC’s
alpha1 is the pore-forming molecule in VDCC’s
Ten types of alpha 1 subunits
Alpha1 subunit has ______ internal repeats, each with ____ transmembrane segments
Alpha1 subunit has four internal repeats, each with six transmembrane segments
L-type Ca++ current go with which channels?
- Cav1.1
- Cav1.2
- Cav1.3
- Cav1.4
P/Q currents are through which Ca++ channels/
- Cav2.1
N-current through which calcium channels?
Cav2.2
R-current through which Ca++ channels?
Cav2.3
T-current through which Ca++ channels?
- Cav3.1
- Cav3.2
- Cav3.3
beta subunit of VDCCs is ____ (ie no membrane spanning region)
beta subunit of VDCCs is hydrophilic (ie no membrane spanning region)
effect of beta subunit of current (VDCC)
increases activation, decreases inactivation
where a gamma subunits of VDCC’s found?
Skeletal muscle
Effect of gamma subunit of VDCC
enhance activation; shift voltage of activation to more negative potentials
delta subunit of VDCC is combined with _____
delta subunit of VDCC is combined with alpha 2
In skeletal muscle alpha2-delta cleaved _______, then bound together with ________
In skeletal muscle alpha2-delta cleaved post-translationally, then bound together with disulphide bridges
