Carbonic anhydrase 8 (CA8)

Carbonic anhydrase 8 is an atypical, enzymatically inactive member of the carbonic anhydrase family. It functions as a crucial allosteric inhibitor of inositol 1,4,5-trisphosphate receptor type-1 (ITPR1), thereby regulating intracellular calcium signaling, neuronal excitability, and synaptic function particularly in sensory neurons. Alternative splicing, controlled by an exon-level cis-eQTL (rs6471859), produces a truncated CA8-204 peptide, which retains inhibitory function against ITPR1, leading to profound analgesic and anti-hyperalgesic effects in animal pain models. CA8-based gene therapy strategies have demonstrated potent non-opioid analgesia in vivo, largely by reducing ER Ca\(^{2+}\) release and activating Kv7 potassium channels to suppress pain signaling. Disruption of CA8 function causes severe neurodevelopmental disorders, but therapeutic augmentation or expression of CA8-204 shows promise for chronic pain treatment without opioid-associated risks[1][2][3][4][6].

Other names

CA8Car8 (murine ortholog)Carbonic anhydrase VIIICA8-204 (truncated peptide isoform)

Allosteric inhibition of ITPR1 (reduces ER calcium release) - Downregulation of cytoplasmic Ca\(^{2+}\), dampening neuronal excitability[1][2][3][4] - Activation of Kv7 potassium channels ("decreases neuronal excitability in nociceptors")[3] - Analgesic effect by attenuating pain signal transmission