Car8, encoding carbonic anhydrase related protein 8, is an acatalytic protein that functions as an allosteric inhibitor of inositol trisphosphate receptor-1 (ITPR1) [3,5]. It is involved in regulating intracellular calcium homeostasis, a process crucial for many cellular functions such as neuronal excitability, neurotransmitter release, and cell fate determination [3,5]. Car8 is expressed in various tissues during mouse embryonic development, including the liver, branchial arches, neuroepithelium, and developing myocardium [6].

In Car8-deficient mouse models, several phenotypes have been observed. Car8wdl null mutant mice show mechanical allodynia and thermal hyperalgesia, with increased steady-state ITPR1 phosphorylation and cytoplasmic free calcium release in dorsal root ganglia (DRG) [5]. In addition, Car8 knockdown in STC-1 cells increases long-chain fatty acid (LCFA)-stimulated GLP-1 secretion, and Car8wdl null mutant mice have a significant increase in GLP-1 response to oral corn oil administration [2]. In the context of spinocerebellar ataxias (SCAs), Car8 was identified as an upregulated gene in one SCA14 mouse model, and its dysfunction causes ataxia in mouse and human [1]. The loss of Car8 in Car8wdl mice also leads to abnormal climbing fiber development in the cerebellum, with premature synapse elimination and delayed translocation at postnatal day 10, though the wiring normalizes by P15 [4].

In conclusion, Car8 plays a vital role in regulating intracellular calcium-related processes, which are essential for normal physiological functions. Gene-knockout mouse models, such as the Car8wdl mouse, have been instrumental in revealing its functions in pain sensation, GLP-1 secretion, and cerebellar development, thereby providing insights into related disease mechanisms like chronic pain and spinocerebellar ataxias [1,2,4,5].

References:

1. Shimobayashi, Etsuko, Kapfhammer, Josef P. . Calcium Signaling, PKC Gamma, IP3R1 and CAR8 Link Spinocerebellar Ataxias and Purkinje Cell Dendritic Development. In Current neuropharmacology, 16, 151-159. doi:10.2174/1570159X15666170529104000. https://pubmed.ncbi.nlm.nih.gov/28554312/

2. Fujiwara, Yuta, Yamane, Shunsuke, Harada, Norio, Hayashi, Yoshitaka, Inagaki, Nobuya. 2021. Carbonic anhydrase 8 (CAR8) negatively regulates GLP-1 secretion from enteroendocrine cells in response to long-chain fatty acids. In American journal of physiology. Gastrointestinal and liver physiology, 320, G617-G626. doi:10.1152/ajpgi.00312.2020. https://pubmed.ncbi.nlm.nih.gov/33533304/

3. Levitt, Roy C, Zhuang, Gerald Y, Kang, Yuan, Martin, Eden R, Wiltshire, Tim. 2017. Car8 dorsal root ganglion expression and genetic regulation of analgesic responses are associated with a cis-eQTL in mice. In Mammalian genome : official journal of the International Mammalian Genome Society, 28, 407-415. doi:10.1007/s00335-017-9694-7. https://pubmed.ncbi.nlm.nih.gov/28547032/

4. Miterko, Lauren N, Sillitoe, Roy V. . Climbing Fiber Development Is Impaired in Postnatal Car8 wdl Mice. In Cerebellum (London, England), 17, 56-61. doi:10.1007/s12311-017-0886-1. https://pubmed.ncbi.nlm.nih.gov/28940157/

5. Zhuang, Gerald Z, Keeler, Benjamin, Grant, Jeff, Martin, Eden R, Levitt, Roy C. 2015. Carbonic anhydrase-8 regulates inflammatory pain by inhibiting the ITPR1-cytosolic free calcium pathway. In PloS one, 10, e0118273. doi:10.1371/journal.pone.0118273. https://pubmed.ncbi.nlm.nih.gov/25734498/

6. Lakkis, M M, Bergenhem, N C, O'Shea, K S, Tashian, R E. . Expression of the acatalytic carbonic anhydrase VIII gene, Car8, during mouse embryonic development. In The Histochemical journal, 29, 135-41. doi:. https://pubmed.ncbi.nlm.nih.gov/9147070/