CACNA1D, encoding the pore-forming α1 subunit of Cav1.3 L-type Ca2+ channels (LTCCs), is crucial for tightly controlled Ca2+ influx through voltage-gated Ca2+ channels. This influx is indispensable for proper physiological functions, including cardiac pacemaking, hearing, hormone secretion, and shaping neuronal firing and plasticity [1,3]. The gene is involved in pathways related to intracellular Ca2+ stability regulation, which is vital for normal cellular activities. Genetic models, such as mouse models, are valuable for studying its function.

Loss-of-function and gain-of-function studies of CACNA1D have revealed its roles in various disease phenotypes. In knock-out mouse models and human mutations, loss of Cav1.3 function did not result in neuropsychiatric or neurological symptoms, while acute selective pharmacological activation led to depressive-like behavior in mice [3]. Germline de novo missense variants in CACNA1D, found in patients with neurodevelopmental and endocrine dysfunction, enhanced Cav1.3 activity. For example, the A749G variant in mice (Cav1.3AG) reproduced many human disease-related abnormalities, including developmental delay, social deficit, and hyperactivity [4]. Mutations in CACNA1D also contribute to diseases like hypertension, congenital hypoglycemia, and autism [1]. In rats, CACNA1D exon mutations led to elevated systolic blood pressure, increased circulating endothelin-1, and vascular, cardiac, and renal remodeling [2].

In conclusion, CACNA1D is essential for normal physiological functions related to Ca2+ influx regulation. Model-based research, especially through KO/CKO mouse models, has shown its significant contribution to understanding diseases such as neurodevelopmental disorders, hypertension, and congenital hyperinsulinism. These studies help in clarifying the gene's role in specific biological processes and disease conditions, providing insights for diagnosis and treatment [1,2,3,4,5].

References:

1. Ortner, Nadine J. . CACNA1D-Related Channelopathies: From Hypertension to Autism. In Handbook of experimental pharmacology, 279, 183-225. doi:10.1007/164_2022_626. https://pubmed.ncbi.nlm.nih.gov/36592224/

2. Wang, Huan, Zhu, Jing-Kang, Cheng, Lan, Maboh, Rene Nfornah, Chen, Hui. . Dominant role of CACNA1D exon mutations for blood pressure regulation. In Journal of hypertension, 40, 819-834. doi:10.1097/HJH.0000000000003085. https://pubmed.ncbi.nlm.nih.gov/35142739/

3. Pinggera, Alexandra, Striessnig, Jörg. 2016. Cav 1.3 (CACNA1D) L-type Ca2+ channel dysfunction in CNS disorders. In The Journal of physiology, 594, 5839-5849. doi:10.1113/JP270672. https://pubmed.ncbi.nlm.nih.gov/26842699/

4. Ortner, Nadine J, Sah, Anupam, Paradiso, Enrica, Roeper, Jochen, Striessnig, Jörg. 2023. The human channel gating-modifying A749G CACNA1D (Cav1.3) variant induces a neurodevelopmental syndrome-like phenotype in mice. In JCI insight, 8, . doi:10.1172/jci.insight.162100. https://pubmed.ncbi.nlm.nih.gov/37698939/

5. Giri, Dinesh, Hawton, Katherine, Senniappan, Senthil. 2021. Congenital hyperinsulinism: recent updates on molecular mechanisms, diagnosis and management. In Journal of pediatric endocrinology & metabolism : JPEM, 35, 279-296. doi:10.1515/jpem-2021-0369. https://pubmed.ncbi.nlm.nih.gov/34547194/