The stromal interaction molecule(STIM)-calcium release-activated calcium channel protein(ORAI) and inositol1,4,5-trisphosphate receptors(IP_3Rs) play pivotal roles in the modulation of Ca^(2+)-regulated pathways from ...The stromal interaction molecule(STIM)-calcium release-activated calcium channel protein(ORAI) and inositol1,4,5-trisphosphate receptors(IP_3Rs) play pivotal roles in the modulation of Ca^(2+)-regulated pathways from gene transcription to cell apoptosis by driving calcium-dependent signaling processes.Increasing evidence has implicated the dysregulation of STIM-ORAI and IP_3Rs in tumorigenesis and tumor progression.By controlling the activities,structure,and/or expression levels of these Ca^(2+)-transporting proteins,malignant cancer cells can hijack them to drive essential biological functions for tumor development.However,the molecular mechanisms underlying the participation of STIM-ORAI and IP_3Rs in the biological behavior of cancer remain elusive.In this review,we summarize recent advances regarding STIM-ORAI and IP_3Rs and discuss how they promote cell proliferation,apoptosis evasion,and cell migration through temporal and spatial rearrangements in certain types of malignant cells.An understanding of the essential roles of STIM-ORAI and IP_3Rs may provide new pharmacologic targets that achieve a better therapeutic effect by inhibiting their actions in key intracellular signaling pathways.展开更多
Calcium-release-activated calcium(CARC)channels are one of the major pathways of calcium entry in non-excitable cells.Despite a decade or two of research,its regulatory mechanism is not yet thoroughly understood.The s...Calcium-release-activated calcium(CARC)channels are one of the major pathways of calcium entry in non-excitable cells.Despite a decade or two of research,its regulatory mechanism is not yet thoroughly understood.The slow progress is due to the complexity of its pores(i.e.,Orai)on one hand and the difficulty in capturing its regulatory complex on the other hand.As a result,possible gating mechanisms have often been speculated by exploring the structure and properties of constitutive open mutants.However,there is much debate about how they can truly reflect the gating of CRAC channels under physiological conditions.In the present study,we combined molecular dynamics simulations with free energy calculations to study three dOrai mutants(G170P,H206A,and P288A),and further calculated their current-voltage curves.Results show that these constructs adopt different approaches to maintain their conductive state.Meanwhile they have unique pore structures and distinctive rectification properties and ion selectivity for cations compared to wild-type pores.We conclude that although the mutants may partially capture the gating motion characteristics of wild-type pores,the information obtained from these mutants is likely not a true reflection of CRAC channel gating under physiological conditions.展开更多
文摘The stromal interaction molecule(STIM)-calcium release-activated calcium channel protein(ORAI) and inositol1,4,5-trisphosphate receptors(IP_3Rs) play pivotal roles in the modulation of Ca^(2+)-regulated pathways from gene transcription to cell apoptosis by driving calcium-dependent signaling processes.Increasing evidence has implicated the dysregulation of STIM-ORAI and IP_3Rs in tumorigenesis and tumor progression.By controlling the activities,structure,and/or expression levels of these Ca^(2+)-transporting proteins,malignant cancer cells can hijack them to drive essential biological functions for tumor development.However,the molecular mechanisms underlying the participation of STIM-ORAI and IP_3Rs in the biological behavior of cancer remain elusive.In this review,we summarize recent advances regarding STIM-ORAI and IP_3Rs and discuss how they promote cell proliferation,apoptosis evasion,and cell migration through temporal and spatial rearrangements in certain types of malignant cells.An understanding of the essential roles of STIM-ORAI and IP_3Rs may provide new pharmacologic targets that achieve a better therapeutic effect by inhibiting their actions in key intracellular signaling pathways.
基金supported by the National Natural Science Foundation of China(No.21773115,No.21833002,No.11771435,and No.22073110)the Natural Science Foundation of Jiangsu Province(No.BK20190056)the Fundamental Research Funds for the Central Universities(021514380018)。
文摘Calcium-release-activated calcium(CARC)channels are one of the major pathways of calcium entry in non-excitable cells.Despite a decade or two of research,its regulatory mechanism is not yet thoroughly understood.The slow progress is due to the complexity of its pores(i.e.,Orai)on one hand and the difficulty in capturing its regulatory complex on the other hand.As a result,possible gating mechanisms have often been speculated by exploring the structure and properties of constitutive open mutants.However,there is much debate about how they can truly reflect the gating of CRAC channels under physiological conditions.In the present study,we combined molecular dynamics simulations with free energy calculations to study three dOrai mutants(G170P,H206A,and P288A),and further calculated their current-voltage curves.Results show that these constructs adopt different approaches to maintain their conductive state.Meanwhile they have unique pore structures and distinctive rectification properties and ion selectivity for cations compared to wild-type pores.We conclude that although the mutants may partially capture the gating motion characteristics of wild-type pores,the information obtained from these mutants is likely not a true reflection of CRAC channel gating under physiological conditions.
