| CACNA1S |
|---|
| Full Name | Calcium Voltage-Gated Channel Alpha Subunit 1S |
| Category | Gene |
| Path | /genes/cacna1s |
| Chromosome | 1q31.3 |
| Protein | L-type calcium channel alpha-1S subunit (CaV1.1) |
| Aliases | CaV1.1, CACNL1A3, HPNS1 |
CACNA1S (Calcium Voltage-Gated Channel Alpha Subunit 1S) encodes the alpha-1S subunit of L-type voltage-gated calcium channels, also known as CaV1.1. This gene is located on chromosome 1q31.3 and is primarily expressed in skeletal muscle. CaV1.1 was the first voltage-gated calcium channel to be characterized and is best known for its essential role in excitation-contraction (EC) coupling.
CACNA1S/CaV1.1 has several critical functions:
CaV1.1 serves as the voltage sensor for skeletal muscle EC coupling:
- Upon depolarization, CaV1.1 undergoes conformational changes
- These changes are directly transmitted to ryanodine receptors (RYR1) on the sarcoplasmic reticulum
- This mechanical coupling triggers calcium release without requiring calcium influx (orthograde EC coupling)
While not its primary function in skeletal muscle:
- CaV1.1 can mediate L-type calcium influx when expressed in other tissues
- In some cell types, contributes to calcium-dependent gene transcription
CaV1.1 is a multimeric complex:
- Alpha-1S subunit: The pore-forming subunit (encoded by CACNA1S)
- Alpha-2 delta subunit: Auxiliary subunit enhancing surface expression
- Beta subunit: Auxiliary subunit regulating gating
- Gamma subunit: Auxiliary subunit with modulatory function
CACNA1S mutations cause several neuromuscular disorders:
- Type 1 (HypoPP1): Most commonly caused by CACNA1S mutations
- Pathogenic mechanism: Mutations cause gain-of-function, leading to abnormal sustained sodium channel inactivation
- Clinical features: Episodic weakness, low serum potassium
- CACNA1S mutations are a recognized cause of MH susceptibility
- Triggered by volatile anesthetics and succinylcholine
- Can lead to life-threatening hyperthermia and rhabdomyolysis
- Thyrotoxic periodic paralysis: Interaction between CACNA1S and thyroid hormone
- Congenital myopathies: Some CACNA1S mutations cause static myopathy
CACNA1S shows highly restricted expression:
- Skeletal muscle: Highest expression in fast-twitch (type II) fibers
- Heart: Minimal expression (CaV1.2/CACNA1C is the primary cardiac L-type channel)
- Brain: Very low expression in specific neuronal populations
- Other tissues: Minor expression in some endocrine tissues
CaV1.1 exhibits unique biophysical characteristics:
- Activation threshold: Relatively positive (~ -20 mV)
- Conductance: High single-channel conductance
- Gating: Slow activation and inactivation kinetics
- Pharmacology: Blocked by dihydropyridines (nifedipine, amlodipine), phenylalkylamines (verapamil), and benzothiazepines (diltiazem)
CaV1.1 is a drug target:
- L-type calcium channel blockers (primarily targeting CaV1.2) are used for hypertension and angina
- Muscle-specific calcium channel modulators for periodic paralysis
- Gene therapy approaches for CACNA1S-related myopathies
- CACNA1S in hypokalemic periodic paralysis (2020)
- Structure of CaV1.1 in complex with beta and alpha2-delta (2020)
- Excitation-contraction coupling mechanism (2019)