PTHR1 (type 1 parathyroid hormone receptors) mediate the effects of PTH (parathyroid hormone) on bone remodelling and plasma Ca2+ homoeostasis. PTH, via PTHR1, can stimulate both AC (adenylate cyclase) and increases in [Ca2+]i (cytosolic free Ca2+ concentration), although the relationship between the two responses differs between cell types. In the present paper, we review briefly the mechanisms that influence coupling of PTHR1 to different intracellular signalling proteins, including the G-proteins that stimulate AC or PLC (phospholipase C). Stimulus intensity, the ability of different PTH analogues to stabilize different receptor conformations (‘stimulus trafficking’), and association of PTHR1 with scaffold proteins, notably NHERF1 and NHERF2 (Na+/H+ exchanger regulatory factor 1 and 2), contribute to defining the interactions between signalling proteins and PTHR1. In addition, cAMP itself can, via Epac (exchange protein directly activated by cAMP), PKA (protein kinase A) or by binding directly to IP3Rs [Ins(1,4,5)P3 receptors] regulate [Ca2+]i. Epac leads to activation of PLCϵ, PKA can phosphorylate and thereby increase the sensitivity of IP3Rs and L-type Ca2+ channels, and cAMP delivered at high concentrations to IP3R2 from AC6 increases the sensitivity of IP3Rs to InsP3. The diversity of these links between PTH and [Ca2+]i highlights the versatility of PTHR1. This versatility allows PTHR1 to evoke different responses when stimulated by each of its physiological ligands, PTH and PTH-related peptide, and it provides scope for development of ligands that selectively harness the anabolic effects of PTH for more effective treatment of osteoporosis.
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February 2012
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Conference Article|
January 19 2012
From parathyroid hormone to cytosolic Ca2+ signals
Colin W. Taylor;
Colin W. Taylor
1
1Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB2 1PD, U.K.
1To whom correspondence should be addressed (email cwt1000@cam.ac.uk).
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Stephen C. Tovey
Stephen C. Tovey
1Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB2 1PD, U.K.
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Publisher: Portland Press Ltd
Received:
June 14 2011
Online ISSN: 1470-8752
Print ISSN: 0300-5127
© The Authors Journal compilation © 2012 Biochemical Society
2012
Biochem Soc Trans (2012) 40 (1): 147–152.
Article history
Received:
June 14 2011
Citation
Colin W. Taylor, Stephen C. Tovey; From parathyroid hormone to cytosolic Ca2+ signals. Biochem Soc Trans 1 February 2012; 40 (1): 147–152. doi: https://doi.org/10.1042/BST20110615
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