The extracellular calcium-sensing receptor(CaSR) is best known for its action in the parathyroid gland and kidneys where it controls body calcium homeostasis. However, the CaSR has different roles in the gastrointesti...The extracellular calcium-sensing receptor(CaSR) is best known for its action in the parathyroid gland and kidneys where it controls body calcium homeostasis. However, the CaSR has different roles in the gastrointestinal tract, where it is ubiquitously expressed. In the colon, the CaSR is involved in controlling multiple mechanisms, including fluid transport, inflammation, cell proliferation and differentiation. Although the expression pattern and functions of the CaSR in the colonic microenvironment are far from being completely understood, evidence has been accumulating that the Ca SR might play a protective role against both colonic inflammation and colorectal cancer. For example, CaSR agonists such as dipeptides have been suggested to reduce colonic inflammation, while dietary calcium was shown to reduce the risk of colorectal cancer. CaSR expression is lost in colonic malignancies, indicating that the CaSR is a biomarker for colonic cancer progression. This dual anti-inflammatory and anti-tumourigenic role of the CaSR makes it especially interesting in colitisassociated colorectal cancer. In this review, we describe the clinical and experimental evidence for the role of the CaSR in colonic inflammation and colorectal cancer, the intracellular signalling pathways which are putatively involved in these actions, and the possibilities to exploit these actions of the CaSR for future therapies of colonic inflammation and cancer.展开更多
AIM： To test the hypothesis that calcium sensing receptor （CASR） polymorphisms are associated with chronic pancreatitis （CP）, and to determine whether serine protease inhibitor Kazal 1type （SPINK1） N34S or alco...AIM： To test the hypothesis that calcium sensing receptor （CASR） polymorphisms are associated with chronic pancreatitis （CP）, and to determine whether serine protease inhibitor Kazal 1type （SPINK1） N34S or alcohol are necessary co-factors in its etiology. METHODS： Initially, 115 subjects with pancreatitis and 66 controls were evaluated, of whom 57 patients and 21 controls were predetermined to carry the high-risk SPINK1 N34S polymorphism. We sequenced CASR gene exons 2, 3, 4, 5 and 7, areas containing the majority of reported polymorphisms and novel mutations. Based on the initial results, we added 223 patients and 239 controls to analyze three common nonsynonymous single nucleotide polymorphisms （SNPs） in exon 7 （A986S, R990G, and Q1011E）. RESULTS： The CASR exon 7 R990G polyrnorphism was significantly associated with CP （OR, 2.01; 95% CI, 1.12-3.59; P = 0.015）. The association between CASR R990G and CP was stronger in subjects who reported moderate or heavy alcohol consumption （OR, 3.12; 95% CI, 1.14-9.13; P = 0.018）. There was no association between the various CASR genotypes and SPINK1 N34S in pancreatitis. None of the novel CASR polymorphisms reported from Germany and India was detected. CONCLUSION： Our United States-based study confirmed an association of CASR and CP and for the first time demonstrated that CASR R990G is a significant risk factor for CP. We also conclude that the risk of CP with CASR R990G is increased in subjects with moderate to heavy alcohol consumption.展开更多
Animal gastrointestinal tract is not only a digestive organ, but also a nutrient sensing organ which detects luminal nutrient and thus can regulate food intake. There are many amino acid sensing receptors and transpor...Animal gastrointestinal tract is not only a digestive organ, but also a nutrient sensing organ which detects luminal nutrient and thus can regulate food intake. There are many amino acid sensing receptors and transporters in the gut. Amino acids sensing by these receptors and transporters can stimulate the intestinal endocrine cells to release a variety of gut hormones. These hormones trigger a series of physiological effects via the nerve system. This review summarized the recent advance on the amino acid sensing receptors and transporters in the gastrointestinal tract, the gut hormones released from the intestinal endocrine cells and the hormones-induced signal transduction between the gut and brain. A better understanding of these processes may help to gain further insight into the specific role of amino acids in digestion and provide guidelines in developing strategy for the better use of amino acids in the diet.展开更多
Calcium-sensing receptor(CaSR),a family C G-protein-coupled receptor,plays a crucial role in regulating calcium homeostasis by sensing small concentration changes of extracellular Ca^(2+),Mg^(2+),amino acids(e.g.,L-Tr...Calcium-sensing receptor(CaSR),a family C G-protein-coupled receptor,plays a crucial role in regulating calcium homeostasis by sensing small concentration changes of extracellular Ca^(2+),Mg^(2+),amino acids(e.g.,L-Trp and L-Phe),small peptides,anions(e.g.,HCO_(3)^(-)and PO_(4)^(3-)),and pH.CaSR-mediated intracellular Ca^(2+)signaling regulates a diverse set of cellular processes including gene transcription,cell proliferation,differentiation,apoptosis,muscle contraction,and neuronal transmission.Dysfunction of CaSR with mutations results in diseases such as autosomal dominant hypocalcemia,familial hypocalciuric hypercalcemia,and neonatal severe hyperparathyroidism.CaSR also influences calciotropic disorders,such as osteoporosis,and noncalciotropic disorders,such as cancer,Alzheimer's disease,and pulmonary arterial hypertension.This study first reviews recent advances in biochemical and structural determination of the framework of CaSR and its interaction sites with natural ligands,as well as exogenous positive allosteric modulators and negative allosteric modulators.The establishment of the first CaSR protein-protein interactome network revealed 94 novel players involved in protein processing in endoplasmic reticulum,trafficking,cell surface expression,endocytosis,degradation,and signaling pathways.The roles of these proteins in Ca^(2+)-dependent cellular physiological processes and in CaSR-dependent cellular signaling provide new insights into the molecular basis of diseases caused by CaSR mutations and dysregulated CaSR activity caused by its protein interactors and facilitate the design of therapeutic agents that target CaSR and other family C G-protein-coupled receptors.展开更多
BACKGROUND Enterotoxins produce diarrhea through direct epithelial action and indirectly by activating the enteric nervous system.Calcium-sensing receptor(CaSR)inhibits both actions.The latter has been well documented...BACKGROUND Enterotoxins produce diarrhea through direct epithelial action and indirectly by activating the enteric nervous system.Calcium-sensing receptor(CaSR)inhibits both actions.The latter has been well documented in vitro but not in vivo.The hypothesis to be tested was that activating CaSR inhibits diarrhea in vivo.AIM To determine whether CaSR agonists ameliorate secretory diarrhea evoked by cholera toxin(CTX)in mice.METHODS CTX was given orally to C57BL/6 mice to induce diarrhea.Calcium and calci-mimetic R568 were used to activate CaSR.To maximize their local intestinal actions,calcium was administered luminally via oral rehydration solution(ORS),whereas R568 was applied serosally using an intraperitoneal route.To verify that their actions resulted from the intestine,effects were also examined on Cre-lox intestine-specific CaSR knockouts.Diarrhea outcome was measured biochemically by monitoring changes in fecal Cl-or clinically by assessing stool consistency and weight loss.RESULTS CTX induced secretory diarrhea,as evidenced by increases in fecal Cl-,stool consistency,and weight loss following CTX exposure,but did not alter CaSR,neither in content nor in function.Accordingly,calcium and R568 were each able to ameliorate diarrhea when applied to diseased intestines.Intestinal CaSR involvement is suggested by gene knockout experiments where the anti-diarrheal actions of R568 were lost in intestinal epithelial CaSR knockouts(villinCre/Casrflox/flox)and neuronal CaSR knockouts(nestinCre/Casrflox/flox).CONCLUSION Treatment of acute secretory diarrheas remains a global challenge.Despite advances in diarrhea research,few have been made in the realm of diarrhea therapeutics.ORS therapy has remained the standard of care,although it does not halt the losses of intestinal fluid and ions caused by pathogens.There is no cost-effective therapeutic for diarrhea.This and other studies suggest that adding calcium to ORS or using calcimimetics to activate intestinal CaSR might represent a novel approach for treating secreto展开更多
Over 1%-15% of the population worldwide is affected by nephrolithiasis,which remains the most common and costly disease that urologists manage today.Identification of atrisk individuals remains a theoretical and techn...Over 1%-15% of the population worldwide is affected by nephrolithiasis,which remains the most common and costly disease that urologists manage today.Identification of atrisk individuals remains a theoretical and technological challenge.The search for monogenic causes of stone disease has been largely unfruitful and a technological challenge;however,several candidate genes have been implicated in the development of nephrolithiasis.In this review,we will review current data on the genetic inheritance of stone disease,as well as investigate the evolving role of genetic analysis and counseling in the management of nephrolithiasis.展开更多
In peripheral artery disease patients,the blood supply directed to the lower limbs is reduced.This results in severe limb ischemia and thereby enhances pain sensitivity in lower limbs.The painful perception is induced...In peripheral artery disease patients,the blood supply directed to the lower limbs is reduced.This results in severe limb ischemia and thereby enhances pain sensitivity in lower limbs.The painful perception is induced and exaggerate during walking,and is relieved by rest.This symptom is termed by intermittent claudication.The limb ischemia also amplifies autonomic responses during exercise.In the process of pain and autonomic responses originating exercising muscle,a number of receptors in afferent nerves sense ischemic changes and send signals to the central nervous system leading to autonomic responses.This review integrates recent study results in terms of perspectives including how nerve growth factor affects muscle sensory nerve receptors in peripheral artery disease and thereby alters responses of sympathetic nerve activity and blood pressure to active muscle.For the sensory nerve receptors,we emphasize the role played by transient receptor potential vanilloid type 1,purinergic P2X purinoceptor 3 and acid sensing ion channel subtype 3 in amplified sympathetic nerve activity responses in peripheral artery disease.展开更多
Calcium-sensing receptor(CaSR),which was initially found in the parathyroid gland,is ubiquitously expressed and exerts specifi c functions in multiple cells,including immune cells.CaSR is functionally expressed on neu...Calcium-sensing receptor(CaSR),which was initially found in the parathyroid gland,is ubiquitously expressed and exerts specifi c functions in multiple cells,including immune cells.CaSR is functionally expressed on neutrophils,monocytes/macrophages,and T lymphocytes,but not B lymphocytes,and regulates cell functions,such as cytokine secretion,chemotaxis,phenotype switching,and ligand delivery.In these immune cells,CaSR is involved in the development of many diseases,such as sepsis,cryopyrin-associated periodic syndromes,rheumatism,myocardial infarction,diabetes,and peripheral artery disease.Since its discovery,it has been controversial whether CaSR is expressed and plays a role in immune cells.This article reviews current knowledge of the role of CaSR in immune cells.展开更多
Objective: To detect the expression changes of proton-sensing receptor G protein-coupled receptor 2A (G2A) and ovarian cancer G protein-coupled receptors 1 (OGR1) in human peripheral blood cells of patients with hypox...Objective: To detect the expression changes of proton-sensing receptor G protein-coupled receptor 2A (G2A) and ovarian cancer G protein-coupled receptors 1 (OGR1) in human peripheral blood cells of patients with hypoxia-induced pulmonary hypertension (HPH). Methods: Thirty-one patients with HPH were enrolled for IPH group, 16 males and 15 females, aged (65.19 ± 5.86) years;and 30 healthy people were enrolled for control group (NC group), 15 males and 15 females, aged (63.47 ± 6.16) years. The peripheral blood samples were collected and the mRNA expressions of G2A and OGR1 were determined by using real-time fluorescent quantitative PCR. The pulmonary arterial pressure (PAP) of HPH group was detected with echocardiography for the analysis of blood gas and pulmonary function testing. Human peripheral blood was collected to detect the mRNA levels of G2A, OGR1 and the serum levels of tumor necrosis factor-α (TNF-α). Results: PaCO2 was increased significantly in HPH group than that in NC group (p < .05). The percentage of forced expiratory volume in 1 s in predicted value (FEV1 pro%) and the ratio of FEV1/forced vital capacity (FVC) in HPH group were significant lower than those in NC group (p < .05). The expressions of peripheral blood G2A mRNA and TNF-α in HPH group were increased dramatically than those in NC group (p < .05). The expressions of OGR1 mRNA in peripheral blood had no difference between HPH group and NC group. The expressions of G2A mRNA and TNF-α in HPH group were positively related to pulmonary artery pressure significantly. Conclusions: The expression of proton-sensing receptor G2A and the level of TNF-α were increased in peripheral blood cells of patients with pulmonary hypertension. The expressions of TNF-α and G2A had positive correlations with pulmonary artery pressure.展开更多
Mechanosensitive ion channels(MSCs)are key molecules in the mechano-electrical transduction of arterial baroreceptors.Among them,acid-sensing ion channel 2(ASIC2)and transient receptor potential vanilloid subfamily me...Mechanosensitive ion channels(MSCs)are key molecules in the mechano-electrical transduction of arterial baroreceptors.Among them,acid-sensing ion channel 2(ASIC2)and transient receptor potential vanilloid subfamily member 1(TRPV1)have been studied extensively and documented to play important roles.In this study,experiments using aortic arch-aortic nerve preparations isolated from rats revealed that both ASIC2 and TRPV1 are functionally necessary,as blocking either abrogated nearly all pressure-dependent neural discharge.However,whether ASIC2 and TRPV1 work in coordination remained unclear.So we carried out cell-attached patch-clamp recordings in HEK293T cells co-expressing ASIC2 and TRPV1 and found that inhibition of ASIC2 completely blocked stretch-activated currents while inhibition of TRPV 1 only partially blocked these currents.Immunofluorescence staining of aortic arch-aortic adventitia from rats showed that ASIC2 and TRPV1 are co-localized in the aortic nerve endings,and co-immunoprecipitation assays confirmed that the two proteins form a compact complex in HEK293T cells and in baroreceptors.Moreover,protein modeling analysis,exogenous co-immunoprecipitation assays,and biotin pull-down assays indicated that ASIC2 and TRPV1 interact directly.In summary,our research suggests that ASIC2 and TRPV1 form a compact complex and function synergisti-cally in the mechano-electrical transduction of arterial baroreceptors.The model of synergism between MSCs may have important biological significance beyond ASIC2 and TRPV 1.展开更多
Calcium sensing receptors (CaSR) is a member of super-family of G-protein coupling receptors. This review first introduced the concept,construction features,distribution,functions,decision methods,moderators,genetic l...Calcium sensing receptors (CaSR) is a member of super-family of G-protein coupling receptors. This review first introduced the concept,construction features,distribution,functions,decision methods,moderators,genetic locus of CaSR and its relationship with some diseases concisely. Then this article described the investigation progress of CaSR in cardiovascular system intensively,including the expression pattern,role and signal pathways of CaSR in rat myocardium in normal,ischemia-reperfusion injury,apoptosis and cardiac hypertrophy; the role and mechanism of CaSR in calcium homostasis regulation of rat myocardium,endoplasmic reticulum (ER) stress and cardiac ischemic preconditioning and postconditioning. The metabolism rule,physiological significance and pathological action of polyamine in cardiac cells; the increase of CaSR expression in cardiac tissue of artherosclerosic rat and its effect on sensitivity to acute myocardial infarction are also discussed. In the end,the research perspective of CaSR in cardiovascular system was anticipated.展开更多
The Ca2+-sensing receptor(the Ca SR),a G-protein-coupled receptor,regulates Ca2+ homeostasis in the body by monitoring extracellular levels of Ca2+([Ca2+]o) and responding to a diverse array of stimuli.Mutations in th...The Ca2+-sensing receptor(the Ca SR),a G-protein-coupled receptor,regulates Ca2+ homeostasis in the body by monitoring extracellular levels of Ca2+([Ca2+]o) and responding to a diverse array of stimuli.Mutations in the Ca2+-sensing receptor result in hypercalcemic or hypocalcemic disorders,such as familial hypocalciuric hypercalcemia,neonatal severe primary hyperparathyroidism,and autosomal dominant hypocalcemic hypercalciuria.Compelling evidence suggests that the Ca SR plays multiple roles extending well beyond not only regulating the level of extracellular Ca2+ in the human body,but also controlling a diverse range of biological processes.In this review,we focus on the structural biology of the Ca SR,the ligand interaction sites as well as their relevance to the disease associated mutations.This systematic summary will provide a comprehensive exploration of how the Ca SR integrates extracellular Ca2+ into intracellular Ca2+ signaling.展开更多
基金Supported by the European Union’s Horizon 2020 research and innovation programme,No.675228the Austrian Science Fund(FWF),No.P 29948-B28
文摘The extracellular calcium-sensing receptor(CaSR) is best known for its action in the parathyroid gland and kidneys where it controls body calcium homeostasis. However, the CaSR has different roles in the gastrointestinal tract, where it is ubiquitously expressed. In the colon, the CaSR is involved in controlling multiple mechanisms, including fluid transport, inflammation, cell proliferation and differentiation. Although the expression pattern and functions of the CaSR in the colonic microenvironment are far from being completely understood, evidence has been accumulating that the Ca SR might play a protective role against both colonic inflammation and colorectal cancer. For example, CaSR agonists such as dipeptides have been suggested to reduce colonic inflammation, while dietary calcium was shown to reduce the risk of colorectal cancer. CaSR expression is lost in colonic malignancies, indicating that the CaSR is a biomarker for colonic cancer progression. This dual anti-inflammatory and anti-tumourigenic role of the CaSR makes it especially interesting in colitisassociated colorectal cancer. In this review, we describe the clinical and experimental evidence for the role of the CaSR in colonic inflammation and colorectal cancer, the intracellular signalling pathways which are putatively involved in these actions, and the possibilities to exploit these actions of the CaSR for future therapies of colonic inflammation and cancer.
基金NIH R01 DK061451 (DCW) and Andrew and Michelle Aloe
文摘AIM： To test the hypothesis that calcium sensing receptor （CASR） polymorphisms are associated with chronic pancreatitis （CP）, and to determine whether serine protease inhibitor Kazal 1type （SPINK1） N34S or alcohol are necessary co-factors in its etiology. METHODS： Initially, 115 subjects with pancreatitis and 66 controls were evaluated, of whom 57 patients and 21 controls were predetermined to carry the high-risk SPINK1 N34S polymorphism. We sequenced CASR gene exons 2, 3, 4, 5 and 7, areas containing the majority of reported polymorphisms and novel mutations. Based on the initial results, we added 223 patients and 239 controls to analyze three common nonsynonymous single nucleotide polymorphisms （SNPs） in exon 7 （A986S, R990G, and Q1011E）. RESULTS： The CASR exon 7 R990G polyrnorphism was significantly associated with CP （OR, 2.01; 95% CI, 1.12-3.59; P = 0.015）. The association between CASR R990G and CP was stronger in subjects who reported moderate or heavy alcohol consumption （OR, 3.12; 95% CI, 1.14-9.13; P = 0.018）. There was no association between the various CASR genotypes and SPINK1 N34S in pancreatitis. None of the novel CASR polymorphisms reported from Germany and India was detected. CONCLUSION： Our United States-based study confirmed an association of CASR and CP and for the first time demonstrated that CASR R990G is a significant risk factor for CP. We also conclude that the risk of CP with CASR R990G is increased in subjects with moderate to heavy alcohol consumption.
基金supported by the National Key Basic Research Program of China (2013CB127300)Natural Science Foundation of China (31430082)+1 种基金Jiangsu Province Natural Science Foundation (BK20130058)the Collaborative Innovation Center of Meat Production and Processing
文摘Animal gastrointestinal tract is not only a digestive organ, but also a nutrient sensing organ which detects luminal nutrient and thus can regulate food intake. There are many amino acid sensing receptors and transporters in the gut. Amino acids sensing by these receptors and transporters can stimulate the intestinal endocrine cells to release a variety of gut hormones. These hormones trigger a series of physiological effects via the nerve system. This review summarized the recent advance on the amino acid sensing receptors and transporters in the gastrointestinal tract, the gut hormones released from the intestinal endocrine cells and the hormones-induced signal transduction between the gut and brain. A better understanding of these processes may help to gain further insight into the specific role of amino acids in digestion and provide guidelines in developing strategy for the better use of amino acids in the diet.
文摘Calcium-sensing receptor(CaSR),a family C G-protein-coupled receptor,plays a crucial role in regulating calcium homeostasis by sensing small concentration changes of extracellular Ca^(2+),Mg^(2+),amino acids(e.g.,L-Trp and L-Phe),small peptides,anions(e.g.,HCO_(3)^(-)and PO_(4)^(3-)),and pH.CaSR-mediated intracellular Ca^(2+)signaling regulates a diverse set of cellular processes including gene transcription,cell proliferation,differentiation,apoptosis,muscle contraction,and neuronal transmission.Dysfunction of CaSR with mutations results in diseases such as autosomal dominant hypocalcemia,familial hypocalciuric hypercalcemia,and neonatal severe hyperparathyroidism.CaSR also influences calciotropic disorders,such as osteoporosis,and noncalciotropic disorders,such as cancer,Alzheimer's disease,and pulmonary arterial hypertension.This study first reviews recent advances in biochemical and structural determination of the framework of CaSR and its interaction sites with natural ligands,as well as exogenous positive allosteric modulators and negative allosteric modulators.The establishment of the first CaSR protein-protein interactome network revealed 94 novel players involved in protein processing in endoplasmic reticulum,trafficking,cell surface expression,endocytosis,degradation,and signaling pathways.The roles of these proteins in Ca^(2+)-dependent cellular physiological processes and in CaSR-dependent cellular signaling provide new insights into the molecular basis of diseases caused by CaSR mutations and dysregulated CaSR activity caused by its protein interactors and facilitate the design of therapeutic agents that target CaSR and other family C G-protein-coupled receptors.
基金Supported by Eunice Kennedy Shriver National Institute of Child Health&Human Development of the National Institutes of Health,No.1K08HD079674-01 and 1R41HD092133-01National Institute of Allergy and Infectious Diseases,No.1A21AI169282and VA Research Career Scientist Award,No.1IK6BX004835.
文摘BACKGROUND Enterotoxins produce diarrhea through direct epithelial action and indirectly by activating the enteric nervous system.Calcium-sensing receptor(CaSR)inhibits both actions.The latter has been well documented in vitro but not in vivo.The hypothesis to be tested was that activating CaSR inhibits diarrhea in vivo.AIM To determine whether CaSR agonists ameliorate secretory diarrhea evoked by cholera toxin(CTX)in mice.METHODS CTX was given orally to C57BL/6 mice to induce diarrhea.Calcium and calci-mimetic R568 were used to activate CaSR.To maximize their local intestinal actions,calcium was administered luminally via oral rehydration solution(ORS),whereas R568 was applied serosally using an intraperitoneal route.To verify that their actions resulted from the intestine,effects were also examined on Cre-lox intestine-specific CaSR knockouts.Diarrhea outcome was measured biochemically by monitoring changes in fecal Cl-or clinically by assessing stool consistency and weight loss.RESULTS CTX induced secretory diarrhea,as evidenced by increases in fecal Cl-,stool consistency,and weight loss following CTX exposure,but did not alter CaSR,neither in content nor in function.Accordingly,calcium and R568 were each able to ameliorate diarrhea when applied to diseased intestines.Intestinal CaSR involvement is suggested by gene knockout experiments where the anti-diarrheal actions of R568 were lost in intestinal epithelial CaSR knockouts(villinCre/Casrflox/flox)and neuronal CaSR knockouts(nestinCre/Casrflox/flox).CONCLUSION Treatment of acute secretory diarrheas remains a global challenge.Despite advances in diarrhea research,few have been made in the realm of diarrhea therapeutics.ORS therapy has remained the standard of care,although it does not halt the losses of intestinal fluid and ions caused by pathogens.There is no cost-effective therapeutic for diarrhea.This and other studies suggest that adding calcium to ORS or using calcimimetics to activate intestinal CaSR might represent a novel approach for treating secreto
文摘Over 1%-15% of the population worldwide is affected by nephrolithiasis,which remains the most common and costly disease that urologists manage today.Identification of atrisk individuals remains a theoretical and technological challenge.The search for monogenic causes of stone disease has been largely unfruitful and a technological challenge;however,several candidate genes have been implicated in the development of nephrolithiasis.In this review,we will review current data on the genetic inheritance of stone disease,as well as investigate the evolving role of genetic analysis and counseling in the management of nephrolithiasis.
基金This work was supported by the National Institutes of Health,No.NIH P01 HL134609 and R01 HL141198(to JL).
文摘In peripheral artery disease patients,the blood supply directed to the lower limbs is reduced.This results in severe limb ischemia and thereby enhances pain sensitivity in lower limbs.The painful perception is induced and exaggerate during walking,and is relieved by rest.This symptom is termed by intermittent claudication.The limb ischemia also amplifies autonomic responses during exercise.In the process of pain and autonomic responses originating exercising muscle,a number of receptors in afferent nerves sense ischemic changes and send signals to the central nervous system leading to autonomic responses.This review integrates recent study results in terms of perspectives including how nerve growth factor affects muscle sensory nerve receptors in peripheral artery disease and thereby alters responses of sympathetic nerve activity and blood pressure to active muscle.For the sensory nerve receptors,we emphasize the role played by transient receptor potential vanilloid type 1,purinergic P2X purinoceptor 3 and acid sensing ion channel subtype 3 in amplified sympathetic nerve activity responses in peripheral artery disease.
基金supported by the National Natural Science Foundation of China for Xinhua Yin and Wenxiu Liu(81370319 and 81700318)the China Postdoctoral Science Foundation for Wenxiu Liu(2018M631957)+2 种基金the Hei Long Jiang Postdoctoral Fund for Wenxiu Liu(LBH-Z17145)Doctor Funds of the First Affi liated Hospital of Harbin Medical University for Wenxiu Liu(201613007)the Innovation and Entrepreneurship Training Program for College Students of Harbin Medical University for Wenxiu Liu(201910226157).
文摘Calcium-sensing receptor(CaSR),which was initially found in the parathyroid gland,is ubiquitously expressed and exerts specifi c functions in multiple cells,including immune cells.CaSR is functionally expressed on neutrophils,monocytes/macrophages,and T lymphocytes,but not B lymphocytes,and regulates cell functions,such as cytokine secretion,chemotaxis,phenotype switching,and ligand delivery.In these immune cells,CaSR is involved in the development of many diseases,such as sepsis,cryopyrin-associated periodic syndromes,rheumatism,myocardial infarction,diabetes,and peripheral artery disease.Since its discovery,it has been controversial whether CaSR is expressed and plays a role in immune cells.This article reviews current knowledge of the role of CaSR in immune cells.
文摘Objective: To detect the expression changes of proton-sensing receptor G protein-coupled receptor 2A (G2A) and ovarian cancer G protein-coupled receptors 1 (OGR1) in human peripheral blood cells of patients with hypoxia-induced pulmonary hypertension (HPH). Methods: Thirty-one patients with HPH were enrolled for IPH group, 16 males and 15 females, aged (65.19 ± 5.86) years;and 30 healthy people were enrolled for control group (NC group), 15 males and 15 females, aged (63.47 ± 6.16) years. The peripheral blood samples were collected and the mRNA expressions of G2A and OGR1 were determined by using real-time fluorescent quantitative PCR. The pulmonary arterial pressure (PAP) of HPH group was detected with echocardiography for the analysis of blood gas and pulmonary function testing. Human peripheral blood was collected to detect the mRNA levels of G2A, OGR1 and the serum levels of tumor necrosis factor-α (TNF-α). Results: PaCO2 was increased significantly in HPH group than that in NC group (p < .05). The percentage of forced expiratory volume in 1 s in predicted value (FEV1 pro%) and the ratio of FEV1/forced vital capacity (FVC) in HPH group were significant lower than those in NC group (p < .05). The expressions of peripheral blood G2A mRNA and TNF-α in HPH group were increased dramatically than those in NC group (p < .05). The expressions of OGR1 mRNA in peripheral blood had no difference between HPH group and NC group. The expressions of G2A mRNA and TNF-α in HPH group were positively related to pulmonary artery pressure significantly. Conclusions: The expression of proton-sensing receptor G2A and the level of TNF-α were increased in peripheral blood cells of patients with pulmonary hypertension. The expressions of TNF-α and G2A had positive correlations with pulmonary artery pressure.
基金by the National Natural Science Foundation of China(31871147 and 31371162)the Science and Technology Development Program of Beijing Municipal Education Commission(KZ202010025038).
文摘Mechanosensitive ion channels(MSCs)are key molecules in the mechano-electrical transduction of arterial baroreceptors.Among them,acid-sensing ion channel 2(ASIC2)and transient receptor potential vanilloid subfamily member 1(TRPV1)have been studied extensively and documented to play important roles.In this study,experiments using aortic arch-aortic nerve preparations isolated from rats revealed that both ASIC2 and TRPV1 are functionally necessary,as blocking either abrogated nearly all pressure-dependent neural discharge.However,whether ASIC2 and TRPV1 work in coordination remained unclear.So we carried out cell-attached patch-clamp recordings in HEK293T cells co-expressing ASIC2 and TRPV1 and found that inhibition of ASIC2 completely blocked stretch-activated currents while inhibition of TRPV 1 only partially blocked these currents.Immunofluorescence staining of aortic arch-aortic adventitia from rats showed that ASIC2 and TRPV1 are co-localized in the aortic nerve endings,and co-immunoprecipitation assays confirmed that the two proteins form a compact complex in HEK293T cells and in baroreceptors.Moreover,protein modeling analysis,exogenous co-immunoprecipitation assays,and biotin pull-down assays indicated that ASIC2 and TRPV1 interact directly.In summary,our research suggests that ASIC2 and TRPV1 form a compact complex and function synergisti-cally in the mechano-electrical transduction of arterial baroreceptors.The model of synergism between MSCs may have important biological significance beyond ASIC2 and TRPV 1.
文摘Calcium sensing receptors (CaSR) is a member of super-family of G-protein coupling receptors. This review first introduced the concept,construction features,distribution,functions,decision methods,moderators,genetic locus of CaSR and its relationship with some diseases concisely. Then this article described the investigation progress of CaSR in cardiovascular system intensively,including the expression pattern,role and signal pathways of CaSR in rat myocardium in normal,ischemia-reperfusion injury,apoptosis and cardiac hypertrophy; the role and mechanism of CaSR in calcium homostasis regulation of rat myocardium,endoplasmic reticulum (ER) stress and cardiac ischemic preconditioning and postconditioning. The metabolism rule,physiological significance and pathological action of polyamine in cardiac cells; the increase of CaSR expression in cardiac tissue of artherosclerosic rat and its effect on sensitivity to acute myocardial infarction are also discussed. In the end,the research perspective of CaSR in cardiovascular system was anticipated.
基金supported by the US National Institutes of Health(GM081749 and EB007268)a Center for Diagnostics and Therapeutics fellowship(to Zhang Chen)funds from the Georgia Research Alliance
文摘The Ca2+-sensing receptor(the Ca SR),a G-protein-coupled receptor,regulates Ca2+ homeostasis in the body by monitoring extracellular levels of Ca2+([Ca2+]o) and responding to a diverse array of stimuli.Mutations in the Ca2+-sensing receptor result in hypercalcemic or hypocalcemic disorders,such as familial hypocalciuric hypercalcemia,neonatal severe primary hyperparathyroidism,and autosomal dominant hypocalcemic hypercalciuria.Compelling evidence suggests that the Ca SR plays multiple roles extending well beyond not only regulating the level of extracellular Ca2+ in the human body,but also controlling a diverse range of biological processes.In this review,we focus on the structural biology of the Ca SR,the ligand interaction sites as well as their relevance to the disease associated mutations.This systematic summary will provide a comprehensive exploration of how the Ca SR integrates extracellular Ca2+ into intracellular Ca2+ signaling.
