Neil Marrion - VGCCs

Question 1

L-type Ca channels

Cav 1.1 - 1.4

Answer 1

HVA

Long-lasting

Cav1.1 = Skeletal - not actually a channel - Ca-sensor for excitation-coupled Ca entry = 19-25 pS

Cav1.2 = Cardiac/neuronal = 19-25 pS

• Helps define shape of cardiac AP
• Neurones, fibroblasts, pancreatic cells

Cav1.3 = Neurones = 36 pS

Cav1.4 = Retina - involved in neurotransmission = 4 pS

More like LVAs = 1.3 + 1.4

Neuronal: 1.2&raquo_space;> 1.3

• Provide Ca-entry for SK channels < 70nm from channels
• Activate calmodulin
• Exhibit CDI!

ALL exhibit VDI

Important for control SCN circadian firing!!
Larger day > night

Question 2

L-type Ca drugs

Answer 2

HVA

DHPs

Agonist = Bay K8644

Inhibitor = Nimidopine/nifedipine

Question 3

N-type

Answer 3

HVA

Neuronal
PNS - neurotransmitter release (not CNS)

Current - activates rapidly!!
Mainly VDI, some CDI

Conotoxin GVIA
Conotoxin MVIIC

Physically interacts with BK channels - co-immunoprecipitate together

Question 4

P/Q-type

Answer 4

Cav2.1

HVA

Purkinje
Involved in NT release at NMJ + CNS NT release

Extensive alternative splicing occurs - P + Q are splice variants = different pharmacology/electrical properties

Little VDI
Some CDI
Some CDF

Conotoxin MVIIC

Blocker = Agotoxin, Conotoxin MVIIC

Question 5

T-type

Answer 5

LVA

Transient
Thalamic oscillations
Small conductance

Fast VDI
No CDI

Underlies high frequency thalamic burst firing during non-REM sleep

No accessory subunits - alpha subunit only!!!

‘Window current’ = sustained T-current

Question 6

Cav2 family

Answer 6

2. 1 = P/Q
3. 2 = N
4. 3 = R

Question 7

R-type

Answer 7

HVA

Cav1.3

Found throughout the brain - particularly the cerebellum

Controls NT release - slower time-scale than N/P-type

Question 8

Auxillary subunit = beta

Answer 8

Traffic/chaperone subunits to the membrane - thereby increasing membrane current

Absence of beta = increased ubiquitation + proteosomal degradation

Question 9

Alpha2-delta1

Answer 9

Enhance currents by increasing alpha1 trafficking to the membrane AND stabilising alpha1 in the membrane

Affects inactivation kinetics
Affects voltage-dependent properties
Affects pharmacology

Pregablin = neuropathic drug - bind alpha2delta, prevent trafficking + reduce NT release + subsequent pain!