6 - Neuronal Ca+ Channels

Question 1

Five roles of Ca++ channels in excitable cells

Answer 1

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

Question 2

In the nerve fibre, the AP has only ____ and ____ components. How is this different from the nerve cell body, nerve terminal and muscle cell?

Answer 2

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

Question 3

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

Answer 3

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

Question 4

Transmitter release is triggered by:

Answer 4

High [Ca++]

Question 5

Why keep intracellular [Ca++] so low («100nM vs 2mM extracellular)
(4)

Answer 5

• 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++

Question 6

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

Answer 6

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

Question 7

What is the role of Ca++ channels in excitable cells?

Answer 7

• 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

Question 8

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

Answer 8

• in neuronal cell bodies, Ca++ enters through Ca++ channels while Na+ enters through Na+ channels during AP
• Elevated [Ca++]i activates gK,Ca’s
• BK channel (gK,Ca) repolarizes neuron during the AP
• AK channel (IAHP) reduces repetitive firing
• Involved in “bursting” behaviour

Question 9

What are Ca++ channels classified by?

Answer 9

Electrical behaviour and
Pharmacology

Question 10

HVA (high voltage activated Ca++) channels start to activate near ___________

Include: ___, ___, ___, ___, __ channels

Answer 10

HVA (high voltage activated Ca++) channels start to activate near AP threshold (about -40mV)

Include: L-, N-, P-, Q-, R- channels

Question 11

LVa (low voltage activated) Ca++ channels start to activate near ____

include ____ channels

Answer 11

LVa (low voltage activated) Ca++ channels start to activate near resting potential (-70mV)

include T channels

Question 12

____ relationships distinguish Ca++ channels

Answer 12

I-V relationships distinguish Ca++ channels

Question 13

Which Ca++ channels have single-channel properties?

Answer 13

T, N, L

Question 14

Where are L-type Ca++ channels found?

Answer 14

• 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++)

Question 15

L-type Ca++ channels are ____ activated

Answer 15

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

Question 16

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

Answer 16

Act as a voltage sensor to trigger Ca++ cascadew

Question 17

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

Answer 17

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

Question 18

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

Answer 18

alpha1C and alpha1D

Question 19

L-type Ca++ channels are blocked by most ____

As well as ____ and ______

Answer 19

L-type Ca++ channels are blocked by most dihydropyridines (nifedipine, nimodipine etc)

Hypertension

Also blocked by verapamil and inorganic blockers (Cd++, Co++, Ni++)

Question 20

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

Answer 20

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

Question 21

L-type Ca++ channels are insensitive to most ____ (commonly used to identify presence of other Ca++ channels)

Answer 21

L-type Ca++ channels are insensitive to most toxins (conotoxins, agatoxins) (commonly used to identify presence of other Ca++ channels)

Question 22

What increases opening probability of L-type Ca++ channels?

Answer 22

• G-protein coupled agonists
  
  • esp beta-adrenergics
    
    • via a cAMP/protein kinase A mechanism
      - phosphorylate channel = increase opening probability

Question 23

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

Answer 23

neurons

(not found in muscle)

Question 24

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

Answer 24

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

Question 25

Inactivation of N-type vs L-type Ca++ channels

Answer 25

N-type inactivate relatively rapidly compared to L-type

Question 26

Pore of N-type Ca++ formed by ____ subunits

Answer 26

Pore of N-type Ca++ formed by* alpha1B* subunits

Question 27

What toxins block N-type Ca++ channels?

Answer 27

- omega-conotoxin G-VI-A - marine cone snail - omega-conotoxin M-VII-C

Question 28

N-type Ca++ channels are insensitive to ____, and ____ (which can block L-type Ca++ channels)

Answer 28

N-type Ca++ channels are insensitive to *dihydropyridines*, and *omega-agatoxin-IV-A (spider)* (which can block L-type Ca++ channels)

Question 29

What decreases the opening probability of N-type Ca++ channels?

Answer 29

- G-protein coupled agonists - eg opioids, alpha2-adrenergics, GABAB agonists

Question 30

Mechanisms to decrease opening probability of N-type channels?

Answer 30

- Direct, voltage sensitive interaction of G-protein betagamma subunits with channel - Indirect, voltage-insesntive modulation of the channel via second messengers - **PRESYNAPTIC INHIBITION**

Question 31

Unlike N-type and L-type Ca++ channels, T-type Ca++ channels prefer ____ over ____

Answer 31

Unlike N-type and L-type Ca++ channels, T-type Ca++ channels prefer *Ca++* over *Ba++*

Question 32

T-type channels are ____-activated

Answer 32

T-type channels are *low voltage*-activated (LVA) - relatively negative voltage of activation

Question 33

T-type Ca++ channels have Rapid ____

Answer 33

T-type Ca++ channels have Rapid *Inactivation* Only open for a short time

Question 34

T-type Ca++ channels require ____ to remove inactivation

Answer 34

T-type Ca++ channels require *strong hyperpolarization* to remove inactivation

Question 35

T-type Ca++ channels are important in ____of cells, not directly in transmitter release

Answer 35

T-type Ca++ channels are important in *Burting behaviour* of cells, not directly in transmitter release

Question 36

T-channels are formed from ____, ____ or ____ subunits

Answer 36

T-channels are formed from *alpha1G*, *alpha1H *or *alpha1I* subunits

Question 37

T-current bursting requires:

Answer 37

Opposing currents, offset in time

Question 38

T-type VDCC makes bursting possible when cell is ____

Answer 38

T-type VDCC makes bursting possible when cell is *hyperpolarized* Does not affect cell when depolarized Slow AP caused by T-current

Question 39

Which inorganic blocker is T-type VDCC most sensitive to?

Answer 39

Nickel (more so than Cd2+ or Co2+)

Question 40

T-type Ca++ channels are blocked by ____

Answer 40

T-type Ca++ channels are blocked by *mibefradil* antihypertensive

Question 41

____ will block T-type VDCC at high concentrations

Answer 41

*dihydropyridines* will block T-type VDCC at high concentrations

Question 42

____ act as T-type channels

Answer 42

*anticonvulsants* act as T-type channels - Ethosuximide metabolites - mehtylphenylsuccinate-MPS - Phenytoin - ^^ block T-type channels

Question 43

T-currents can be modulated by ____

Answer 43

T-currents can be modulated by *G-protein coupled agonists* - Inhibition by Gbeta-gamma coupling - PKC family inhibits - Dopamine (DA), somatostatin, Angiotensin II

Question 44

P/Q-type Ca++ channel nomenclature arose from ____ where they were first described

Answer 44

P/Q-type Ca++ channel nomenclature arose from *purkinje cells* (large GABAergic cells of cerebellum) where they were first described

Question 45

P/Q type VDCC prefer conducting ____ over Ca++

Answer 45

P/Q type VDCC prefer conducting *Ba++* over Ca++

Question 46

____forms pore of P/Q-type Ca++ channels

Answer 46

*alpha1A* forms pore of P/Q-type Ca++ channels

Question 47

P/Q-type VDCC's are important in ____ of purkinje cell dendrites

Answer 47

P/Q-type VDCC's are important in *bursting behavior* of purkinje cell dendrites

Question 48

Describe A-E

Answer 48

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

Question 49

P/Q-type VDCCs require ____ to deactivate

Answer 49

P/Q-type VDCCs require *relatively strong hyperpolarization *to deactivate Inactivates rapidly

Question 50

What forms the pore of R-type VDCCs

Answer 50

Alpha1E

Question 51

R-type VDCC's are resistant to:

Answer 51

Most toxins (conotoxins, agatoxins)

Question 52

R-type VDCCs are modulated by ____

Answer 52

some agonists

Question 53

VDCCs are made up of several subunits: ___, ___, ___, ___, ___

Answer 53

VDCCs are made up of several subunits: *alpha1, alpha 2, beta, gamma, delta*

Question 54

____ is the pore-forming molecule in VDCC's

Answer 54

*alpha1* is the pore-forming molecule in VDCC's Ten types of alpha 1 subunits

Question 55

Alpha1 subunit has ____ internal repeats, each with ____ transmembrane segments

Answer 55

Alpha1 subunit has *four* internal repeats, each with *six* transmembrane segments

Question 56

L-type Ca++ current go with which channels?

Answer 56

- Cav1.1 - Cav1.2 - Cav1.3 - Cav1.4

Question 57

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

Answer 57

- Cav2.1

Question 58

N-current through which calcium channels?

Answer 58

- Cav2.2

Question 59

R-current through which Ca++ channels?

Answer 59

- Cav2.3

Question 60

T-current through which Ca++ channels?

Answer 60

- Cav3.1 - Cav3.2 - Cav3.3

Question 61

beta subunit of VDCCs is ____ (ie no membrane spanning region)

Answer 61

beta subunit of VDCCs is hydrophilic (ie no membrane spanning region)

Question 62

effect of beta subunit of current (VDCC)

Answer 62

increases activation, decreases inactivation

Question 63

where a gamma subunits of VDCC's found?

Answer 63

Skeletal muscle

Question 64

Effect of gamma subunit of VDCC

Answer 64

enhance activation; shift voltage of activation to more negative potentials

Question 65

delta subunit of VDCC is combined with ____

Answer 65

delta subunit of VDCC is combined with *alpha 2*

Question 66

In skeletal muscle *alpha2-delta* cleaved ____, then bound together with ____

Answer 66

In skeletal muscle *alpha2-delta* cleaved *post-translationally,* then bound together with *disulphide bridges*