Carbonic anhydrase VIII as a regulator of intracellular calcium signaling: mechanistic insights and implications in human disease.

Carbonic anhydrases are classically defined as zinc-dependent enzymes that catalyze the reversible hydration of carbon dioxide and play essential roles in acid-base homeostasis. However, carbonic anhydrase VIII (CA VIII) represents a catalytically inactive member of this family due to the absence of one of the three histidine residues required for enzymatic activityStructural analyses further indicate that, despite this loss of catalytic function, CA VIII retains the conserved carbonic anhydrase fold, suggesting functional repurposing rather than structural degeneration. Despite this catalytic silencing, CA VIII is evolutionarily conserved and highly expressed in neuronal tissues, indicating important biological functions beyond enzymatic catalysis. Converging structural, biochemical, and genetic evidence supports the view that CA VIII functions as a pseudoenzyme that regulates intracellular signaling pathways. Mechanistically, CA VIII interacts with the inositol 1,4,5-trisphosphate receptor type 1 (IP3R1), modulating intracellular calcium release and thereby influencing neuronal excitability, synaptic function, and cerebellar development. Disruption of CA VIII has been consistently associated with altered calcium homeostasis and impaired neuronal signaling. Importantly, human genetic studies provide direct evidence for the physiological significance of CA VIII. Mutations identified in affected families, including reports from Iraqi and Saudi Arabian populations, are associated with cerebellar ataxia and neurodevelopmental abnormalities, linking CA VIII dysfunction to human disease. These findings establish CA VIII as a critical regulator of neuronal calcium signaling with clear clinical relevance. In this review, we integrate structural, molecular, and genetic evidence to position CA VIII as a functionally repurposed pseudoenzyme that operates as a signaling regulator rather than a catalytic enzyme. We further discuss its emerging roles in neuronal physiology and disease, and highlight broader implications for pseudoenzyme biology and the evolution of protein function.