CACNB4 encodes the beta-4 auxiliary subunit of voltage-gated calcium channels, functioning as a critical regulator of calcium channel activity and neuronal gene expression. As a calcium channel auxiliary subunit, CACNB4 modulates peak calcium current, voltage-dependent activation and inactivation, G-protein inhibition, and membrane targeting of the alpha-1 subunit 1. Beyond its classical electrophysiological role, CACNB4 couples neuronal electrical activity to gene transcription through a nuclear signaling pathway: electrical stimulation triggers CACNB4 nuclear translocation via interaction with the PP2A phosphatase regulatory subunit Ppp2r5d, enabling association with gene promoters and histone modification to regulate transcription 2. CACNB4 mutations cause multiple neurological channelopathies. The R482X truncation mutation impairs nuclear translocation and PP2A interaction, causing juvenile myoclonic epilepsy 2. The missense mutation C104F is associated with generalized epilepsy and episodic ataxia 3. Additionally, CACNB4 mutations cause episodic ataxia type 5, characterized by paroxysmal ataxia responsive to acetazolamide treatment 4. Recent evidence suggests CACNB4 represents a druggable target for periodontitis, with verapamil and safinamide showing potential to inhibit osteoclast differentiation 5.