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
Astrocytes＇ roles in late-onset Alzheimer＇s disease （LOAD） promotion are important, since they survive soluble or fibrillar amyloid-β peptides （Aβs） neurotoxic effects, undergo alterations of intracellular and...Astrocytes＇ roles in late-onset Alzheimer＇s disease （LOAD） promotion are important, since they survive soluble or fibrillar amyloid-β peptides （Aβs） neurotoxic effects, undergo alterations of intracellular and intercellular Ca2＋ signaling and gliotransmitters release via the Aβ/a7-nAChR （αT-nicotinic acetylcholine receptor） signaling, and overproduce/oversecrete newly synthesized Aβ42 oligomers, NO, and VEGF-A via the Aβ/CaSR （calcium-sensing receptor） signaling. Recently, it was suggested that the NMDAR （N-methyl-D-aspartate receptor） inhibitor nitromemantine would block the synapse-destroying effects of Aβ/α7-nAChR signaling. Yet, this and the progressive extracellular accrual and spreading of Aβ42 oligomers would be stopped well upstream by NPS 2143, an allosteric CaSR antagonist （calcilytic）.展开更多
Autosomal dominant hypocalcemia(ADH)type 1 and 2 are disorders of calcium homeostasis caused by gain of function variants.The calcium-sensing receptor(CaSR)is a class C GPCR that responds to elevated extracellular cal...Autosomal dominant hypocalcemia(ADH)type 1 and 2 are disorders of calcium homeostasis caused by gain of function variants.The calcium-sensing receptor(CaSR)is a class C GPCR that responds to elevated extracellular calcium(Ca^(2+)o)by inhibiting parathyroid hormone(PTH)secretion and promoting renal excretion of Ca^(2+)and other salts to restore physiologically normal Ca^(2+)o concentrations.CaSR negative allosteric modulators(NAMs)transiently raise PTH levels in individuals with ADH1,restoring Ca^(2+)o concentration to a physiological normal range.Herein we disclose the discovery of a chemoreactive NAM(ATF936-NCS,4)for the CaSR that(i)is wash-resistant indicative of irreversible receptor binding and(ii)stimulates prolonged PTH release in vivo.This‘first-in-class’chemical probe will provide invaluable insight towards the development of longer acting NAMs for the treatment of ADH.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.
文摘Astrocytes＇ roles in late-onset Alzheimer＇s disease （LOAD） promotion are important, since they survive soluble or fibrillar amyloid-β peptides （Aβs） neurotoxic effects, undergo alterations of intracellular and intercellular Ca2＋ signaling and gliotransmitters release via the Aβ/a7-nAChR （αT-nicotinic acetylcholine receptor） signaling, and overproduce/oversecrete newly synthesized Aβ42 oligomers, NO, and VEGF-A via the Aβ/CaSR （calcium-sensing receptor） signaling. Recently, it was suggested that the NMDAR （N-methyl-D-aspartate receptor） inhibitor nitromemantine would block the synapse-destroying effects of Aβ/α7-nAChR signaling. Yet, this and the progressive extracellular accrual and spreading of Aβ42 oligomers would be stopped well upstream by NPS 2143, an allosteric CaSR antagonist （calcilytic）.
基金supported by the Australian Research Council(No.DP170104228)the National Health and Medical Research Council of Australia(No.1138891)+1 种基金KL and KJG are Australian Research Council Future Fellows(fellowships FT160100075 and FT170100392,respectively)TMJ is a National Health and Medical Research Council Emerging Leader Fellow(fellowship 2008341,Australia).
文摘Autosomal dominant hypocalcemia(ADH)type 1 and 2 are disorders of calcium homeostasis caused by gain of function variants.The calcium-sensing receptor(CaSR)is a class C GPCR that responds to elevated extracellular calcium(Ca^(2+)o)by inhibiting parathyroid hormone(PTH)secretion and promoting renal excretion of Ca^(2+)and other salts to restore physiologically normal Ca^(2+)o concentrations.CaSR negative allosteric modulators(NAMs)transiently raise PTH levels in individuals with ADH1,restoring Ca^(2+)o concentration to a physiological normal range.Herein we disclose the discovery of a chemoreactive NAM(ATF936-NCS,4)for the CaSR that(i)is wash-resistant indicative of irreversible receptor binding and(ii)stimulates prolonged PTH release in vivo.This‘first-in-class’chemical probe will provide invaluable insight towards the development of longer acting NAMs for the treatment of ADH.
