{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n CACNA1D encodes the pore‐forming α₁ subunit of the L‐type voltage‐gated calcium channel CaV1.3, a channel that plays a central role in mediating Ca²⁺ influx to control a wide range of physiological processes. In the adrenal glomerulosa, gain‐of‐function mutations in CACNA1D shift the voltage dependence to more negative potentials and/or impair channel inactivation, thereby increasing intracellular Ca²⁺ and stimulating aldosterone production. These alterations contribute to the formation of aldosterone‐producing adenomas and primary aldosteronism."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In neuronal tissues, CaV1.3 channels are critical for synaptic integration and plasticity. They are modulated by G‐protein–coupled receptors—including dopamine D2 and muscarinic M1 receptors—in striatal medium spiny neurons, thereby influencing neuronal excitability and signaling."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": " Moreover, alternative splicing of CACNA1D generates distinct isoforms with modified gating properties that allow channel activation at lower threshold potentials. This splicing‐based modulation finely tunes Ca²⁺ signaling in diverse cellular contexts."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In the auditory system, CaV1.3 channels account for the vast majority of Ca²⁺ currents in hair cells, and mutations in CACNA1D have been linked to a syndrome characterized by congenital deafness and sinoatrial node dysfunction (SANDD), underscoring its essential role in auditory signal transduction and cardiac pacemaking."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Furthermore, recent genetic association studies have implicated CACNA1D variants in blood pressure regulation, suggesting that the proper function of CaV1.3 channels is also important in maintaining cardiovascular homeostasis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Finally, de novo gain‐of‐function mutations in CACNA1D have been identified in patients with neurodevelopmental disorders such as autism and intellectual disability, often in conjunction with neuroendocrine abnormalities and seizures. This highlights a growing appreciation for CACNA1D dysregulation as a common pathophysiological mechanism across endocrine, neuronal, and auditory systems."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Collectively, these findings underscore the multifaceted role of CACNA1D in regulating Ca²⁺ influx in diverse tissues and establish its dysfunction as a key contributor to conditions ranging from primary aldosteronism and hypertension to congenital deafness and neurodevelopmental disorders.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Ute I Scholl, Gerald Goh, Gabriel Stölting, et al. 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