Gene Number: 775

Location: 12p13.33

Key Functions: Voltage-gated calcium influx, cardiac excitation–contraction coupling, neuronal excitability, intracellular signaling and gene transcription regulation

CACNA1C encodes the alpha-1C subunit of the L-type voltage-gated calcium channel (Cav1.2), which plays a central role in the physiology of excitable tissues by mediating the influx of calcium ions into cells upon membrane depolarization. When a cell reaches a threshold potential, Cav1.2 channels open, permitting Ca²⁺ entry that initiates a cascade of intracellular signaling events fundamental to numerous cellular functions [R].

These channels are crucial for [R]:

1. Initiating muscle contractions, particularly in the heart:The alpha-1C subunit forms the pore through which calcium ions enter cardiac muscle cells, triggering further release of calcium from the sarcoplasmic reticulum — a process known as calcium-induced calcium release. This mechanism underlies cardiac excitation–contraction coupling, maintaining rhythmic heartbeat and ensuring efficient cardiac output. Cav1.2 channels also contribute to the plateau phase of the cardiac action potential, helping regulate contractility and electrical stability of the myocardium.

2. Regulating neuronal activity in the brain:In neurons, Cav1.2 channels participate in controlling membrane excitability and synaptic signaling. Their activation allows calcium entry that contributes to neurotransmitter release, dendritic signaling, and the activation of calcium-dependent transcription factors such as CREB and NFAT. Through these pathways, CACNA1C influences neuronal plasticity, cognitive processing, mood regulation, and memory formation — thereby serving as a key modulator of central nervous system function.

Mutations or dysregulation of CACNA1C are associated with a broad spectrum of disorders, highlighting its physiological importance in both cardiac and neurological health [R].

• Timothy syndrome results from specific gain-of-function mutations in CACNA1C that prolong calcium channel opening, causing severe cardiac arrhythmias (notably long QT syndrome type 8), structural heart defects, syndactyly, and neurodevelopmental abnormalities.

• Other cardiac channelopathies, including Brugada syndrome and certain forms of idiopathic long QT syndrome, have been linked to pathogenic variants of CACNA1C that alter calcium current kinetics or membrane expression.

• In the central nervous system, genetic and functional studies implicate altered CACNA1C expression and signaling in bipolar disorder, schizophrenia, and major depressive disorder, suggesting that Cav1.2-mediated calcium signaling contributes to the pathophysiology of these complex psychiatric conditions.

  
  

Understanding the intricate functions of CACNA1C not only illuminates its essential roles in maintaining normal cardiac rhythm and neuronal function but also emphasizes its clinical significance across diverse disease domains. Continued research into the molecular and regulatory mechanisms of Cav1.2 may foster the development of targeted therapies aimed at modulating calcium signaling pathways for the prevention and treatment of related cardiovascular and neuropsychiatric disorders [R].