CACNA1D and Associated Diseases

Calcium channel, voltage-dependent, L type, alpha 1D subunit (also known as Ca_v 1.3) is a protein that in humans is encoded by the CACNA1D gene, and the voltage-dependent calcium channel is a polyprotein composed of four subunits. The structure, in which the α1 subunit is the decisive group, distinguishes the Ca_v 1.3 channel from other members of this family and provides a unique selective control, voltage sensor, and gating device for voltage-gated calcium channels (VGCCs).

The subunit expressed by the CACNA1D gene is the α1-D subunit, which is widely present in neurons with different electrical activity patterns and provides L-type calcium currents. Specifically, α1-D confers low-voltage-activated and slowly-inactivated calcium currents and is suitable for specific physiological functions.

CACNA1D in Hearing

The unique L-shaped current of the Ca_v 1.3 channel is well suited for the neurotransmitter release process of inner hair cells of the cochlea. Patch-clamp experiments show that normal expression of Ca_v 1.3 channels is critical for proper hearing development and synaptic transmission processes.

CACNA1D in Chromaffin Cells

Recent studies have demonstrated that Ca channels are densely expressed in chromaffin cells, and the low-voltage activation and slow inactivation modes of these channels are ideal for controlling chromaffin cell excitability. It was also found that catecholamines are particularly sensitive to L-type currents, and L-type channels are responsible for the exocytosis of related cells.

In addition, disease-specific whole-exome sequencing studies revealed that missense mutations in CACNA1E led to enhanced calcium signaling in Ca_v 1.3 channels and pose a significant risk to patients.

Fig 1. CACNA1D mutations reported in human diseases. (Pinggera, 2016)

CACNA1D in Neurological Diseases

Ca_v 1.3 is abundantly expressed in the central nervous system and shapes neuronal firing and plasticity. Recent sequencing studies have shown that mutations in the CACNA1D gene contributed to the risk of developing neurological diseases, including Parkinson's disease due to the death of dopaminergic neurons, or epilepsy due to increased neural sensitivity.

CACNA1D in Prostate Cancer

The latest results of immunostaining experiments show that CACNA1D is highly expressed in prostate cancer cells compared to benign prostate tissue and that blocking the L-type channel or inhibiting the expression of this gene could significantly inhibit cell growth in prostate cancer cells.

CACNA1D in Other Diseases

Missense mutations in CACNA1D result in additional sensitivity of CaV 1.3 channels and may contribute to sinus node dysfunction and deafness syndrome, primary aldosteronism, autism spectrum disorder, etc.

Fig 2. CACNA1D variants permit enhanced channel function of Ca_v 1.3 L-type Ca²⁺ channels. (Ortner, 2020)

References

1. Pinggera, A.; Striessnig, J. CaV 1.3 (CACNA1D) L-type Ca2+ channel dysfunction in CNS disorders. The Journal of Physiology. 2016, 20: 5839-5849.
2. Ortner, N.J.; et al. De novo CACAN1D Ca²⁺ channelopathies: clinical phenotypes and molecular mechanism. European Journal of Physiology. 2020, 472: 755-773.