Voltage-gated Ca2+ Channels.
By: Leslie Samuel
Molecular and Developmental Neurobiology
Introduction:
- Is calcium important?
1. Muscle Contraction, transmitter release, electrical spiking behavior
and gene expression
2. Mutations Wide range of neurological and motor diseases,
e.g.Malignant hyperthermia, hypokalemic periodic paralysis.
- Two main sources of Calcium:
1. Endoplasmic reticulum.
2. Extracellular space.
- Primary mechanism of getting calcium across plasma membrane: V-gated
Ca2+ channels.
History:
- Paul Fatt and Bernard Katz (1953): discovered Ca2+ Channels (but didn’t
know). Experiments with crayfish muscle fibers
- Fatt and Ginsborg (1958): Removed Na+ and Ca2+ from Ringer
Calcium is important
- Hagiwara, Ozawa and Sand (1975): Different types of Ca2+ channels
- Hagiwara and Byerly (1981): Voltage-clamp recording  Biophysics
- Nowycky, Fox and Tsien (1985). 3 Types
Different Voltage gated Calcium Channels:
1. T-Type (Transient) channels:
a. Activation: Low Threshold, Rapid inactivation
b. Found in cardiac and vascular smooth muscle
c. Sensitive to dihydropyridines
2. N- Type (Neuron) channels:
a. Blocked by GVIA
b. Found in the neuron
c. DHP-insensitive
d. Irreversibly blocked by w-CgTx
3. L-Type (Long Lasting) channels
a. Voltage activation at relatively depolarized voltages and slow
inactivation
b. Sensitive to dihydropyridines
c. Reversibly blocked by w-conotoxin (w-CgTx)
4. P-Type Channels:
a. DHP- and w-CgTX insensitive
b. Sensitive to toxins in venom from funnel web spiders.
Molecular Structure:
4 Subunits:
2. 1 Subunit
a. Main subunit. Structurally similar to Na+ channel.
b. Transmembrane
c. Consists of 4 internal repeated domains
d. Domain I: responsible for channel activation kinetics
e. S4 makes up the voltage sensor - highly charged.
f. P domain makes up the pore.
3.  Subunit
a. Membrane Spanning
b. Regulatory function
i. Increases amplitude of Ca2+ currents
4.  Subunit
a. Intracellular, cytoplasmic
b. Regulatory functions
5.  Subunit
a. Membrane spanning. No cytoplasmic domain
b. Regulatory functions
i. Produce small increase in peak Ca2+ currents and
activation rates
ii. Shift activation to more hyperpolarized membrane
potentials