Car8, encoding carbonic anhydrase related protein 8, lacks enzymatic activity but functions as an allosteric inhibitor of inositol trisphosphate receptor-1 (ITPR1), regulating intracellular calcium release crucial for synaptic functions and neuronal excitability [3]. It is involved in pathways like PLC/IP3/Ca2+ and is important for processes such as Purkinje cell dendritic development, GLP-1 secretion, and pain regulation [1,2,5]. Genetic models, especially mouse models, have been instrumental in studying its functions.

In Car8-deficient mouse models, there are significant phenotypic changes. For instance, Car8wdl null mutant mice show increased GLP-1 response to oral corn oil administration, indicating that Car8 negatively regulates GLP-1 secretion from preproglucagon-expressing cells via the PLC/IP3/Ca2+ pathway [2]. Car8 null mutant mice also exhibit mechanical allodynia and thermal hyperalgesia, with increased steady-state ITPR1 phosphorylation and cytoplasmic free calcium release in dorsal root ganglia, suggesting its role in pain regulation [5]. In the Car8wdl mouse model of hereditary ataxia, there are initial defects in cerebellar development, though the cerebellum shows some compensation in size and morphology later. However, persistent motor dysfunction remains, along with abnormal neuronal and muscle activity [4].

In conclusion, Car8 is essential for regulating GLP-1 secretion, pain perception, and cerebellar function. Studies using Car8 KO mouse models have revealed its role in these biological processes, providing insights into diseases such as diabetes, chronic pain, and spinocerebellar ataxias.