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_K,Ca's _BK channel (g_K,Ca_)_ repolarizes neuron during the AP _AK channel (I_AHP_)_ reduces repetitive firing Involved in “_bursting_” behaviour

6 - Neuronal Ca Channels Flashcards by Echo Quinton

Five roles of Ca++ channels in excitable cells

Intracellular signals
1. Ca++ - dependent enzymes
2. Gene regulation
Transmitter release
Electrical behaviour
1. effects of Ca++ as charge carrier (intracellular messenger)
2. Effects of Ca++ on other membrane ion channels
Neurite outgrowth
Muscle contraction

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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

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Enzymes such as _____ and _____ are activated by Ca++ (intracellular messenger)

Enzymes such as protien kinases and proteases are activated by Ca++ (intracellular messenger)

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Transmitter release is triggered by:

High [Ca++]

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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++

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What is the importance of local [Ca++] in Ca++ domains?

locally high concentration (near Ca++ source) = local actions

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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 g_K,Ca’s
BK channel (g_K,Ca) repolarizes neuron during the AP
AK channel (I_AHP) reduces repetitive firing
Involved in “bursting” behaviour

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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_{K,Ca's}
BK channel (g_K,Ca) repolarizes neuron during the AP
AK channel (I_AHP) reduces repetitive firing
Involved in “bursting” behaviour

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What are Ca++ channels classified by?

Electrical behaviour and
- Pharmacology

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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

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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

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_____ relationships distinguish Ca++ channels

I-V relationships distinguish Ca++ channels

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Which Ca++ channels have single-channel properties?

T, N, L

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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++)

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L-type Ca++ channels are _______ activated

L-type Ca++ channels are high voltage activated (~-40mV)

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L-type Ca++ have what role in muscles?

Act as a voltage sensor to trigger Ca++ cascadew

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L-type Ca++ channels prefer to pass ___ rather than Ca++

L-type Ca++ channels prefer to pass Ba++ rather than Ca++

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What are the pore-forming subunits in L-type Ca++ channels?

alpha1C and alpha1D

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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++)

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__________ agonists such as BAYK-8644 will open L-type Ca++ channels

dihydropyridine agonists such as BAYK-8644 will open L-type Ca++ channels

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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)

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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

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Where are N-type Ca++ channels most commonly found?

neurons

(not found in muscle)

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Open time of N-type Ca++ channels vs L-type Ca++ channels?

N-type Ca++ channels have a shorter open time than L-type

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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__1B 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, GABA_B 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__1G_, alpha__1H or _alpha__1I 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 G_beta-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__1A 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

Alpha_1E

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?

* Ca_v1.1 * Ca_v1.2 * Ca_v1.3 * Ca_v1.4

P/Q currents are through which Ca++ channels/

* Ca_v2.1

N-current through which calcium channels?

Ca_v2.2

R-current through which Ca++ channels?

Ca_v2.3

T-current through which Ca++ channels?

* Ca_v3.1 * Ca_v3.2 * Ca_v3.3

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_