PMID:23576580

Citation	'Linde, CI, Feng, B, Wang, JB and Golovina, VA (2013) Histidine triad nucleotide-binding protein 1 (HINT1) regulates Ca2+ signaling in mouse fibroblasts and neuronal cells via store-operated Ca2+ entry pathway. Am. J. Physiol., Cell Physiol. '
Abstract	Recent findings indicate that histidine triad nucleotide-binding protein 1 (HINT1) is implicated in the pathophysiology of certain psychiatric disorders, and also exhibits tumor suppressor properties. However, the authentic functions of HINT1 in cellular physiology and especially its role in Ca(2+) signaling remain unclear. Here, we studied Ca(2+) signaling in cultured embryonic fibroblasts derived from wild type control and HINT1 knockout (KO) mice. Resting cytosolic Ca(2+) level (measured with fura-2) was not altered in fibroblasts lacking HINT1. The stored Ca(2+) evaluated by measuring peak amplitude of ATP (10µM)-induced Ca(2+) transients in Ca(2+)-free medium was significantly larger in HINT1 KO fibroblasts than in wild-type cells. Ca(2+) influx after external Ca(2+) restoration, likely via store- and receptor-operated channels (SOCs and ROCs, respectively), was greatly (by 2-fold) reduced in HINT1 KO fibroblasts. This correlated with a down-regulated expression of Orai1 and stromal interacting molecule 1 (STIM1), essential components of store-operated Ca(2+) entry pathway. Expression of C-type transient receptor potential TRPC3 and TRPC6, which function as ROCs, was not altered in HINT1 KO fibroblasts. Immunoblots also revealed that Orai1 was down-regulated by 2-fold in brain lysates of HINT1 KO mice in comparison with the wild-type littermates. Importantly, silencer RNA knockdown of HINT1 in Neuro-2A cells markedly down-regulated Orai1 and STIM1 protein expression and significantly (by 2.5-fold) reduced ATP-induced Ca(2+) influx, while ATP-evoked Ca(2+) release was not changed. Thus, the study demonstrates a novel function of HINT1 that involves the regulation of SOC-mediated Ca(2+) entry pathway (Orai1, STIM1), essential for regulation of cellular Ca(2+) homeostasis.
Links	PubMed Online version:10.1152/ajpcell.00073.2013
Keywords
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
MOUSE:HINT1		GO:0050850: positive regulation of calcium-mediated signaling	ECO:0000315:		P		Fig. 2A,B, along with Fig. 1B show that the HINT1 KO fibroblasts demonstrate calcium ion dysregulation, While the immunoblots displayed in Fig. 3A-D, revealed that the decreased ATP-induced Ca2+ entry is likely a consequence of down-regulated expression of Orai1 and STIM1 proteins.	complete CACAO 7931
MOUSE:HINT1	involved_in	GO:0050850: positive regulation of calcium-mediated signaling	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete

References

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