Structurally Diverse N-terminal Peptides of Parathyroid Hormone (PTH) and PTH-related Peptide (PTHRP) Inhibit the Na+/H+ Exchanger NHE3 Isoform by Binding to the PTH/PTHRP Receptor Type I and Activating Distinct Signaling Pathways

Abstract

N-terminal peptides of parathyroid hormone (PTH) and PTH-related peptide (PTHRP) elicit a wide variety of biological responses in target cells, including the inhibition of Na

Dual Signaling and Ligand Selectivity of the Human PTH/PTHrP Receptor

“…hPTH failed to activate AC at all concentrations tested in both cell lines, whereas the response to hPTHrP(1-36) again was indistinguishable from that to hPTH . These results, which contrast with previous reports in rodent systems, (10,11,25,33,34) indicate that hPTH(3-34) retains partial agonism for AC via abundantly expressed hPTHRs but that it does not stimulate PLC via these receptors.…”

“…(21) These and other studies (24) have emphasized the possible involvement of PLC-independent mechanisms in generating some intracellular calcium responses via the hPTHR. Reports of the actions of PTH , a putative PLC/PKC-selective analog, (10,11,17,18,25) via recombinant hPTHRs in these systems, are contradictory. Direct measurements of PTH(3-34)-stimulated PLC activation via expressed hPTHRs have not been reported.…”

“…(14,(16)(17)(18) Others have employed PTH to probe the involve-ment of PKC in the regulation of renal ion transporters and enzymes by PTH in rat and opposum kidney cells. (10,12,15) The ligand selectivity and signaling properties of the human PTHR (hPTHR) have not been widely studied. Transfected recombinant hPTHRs expressed in COS-7 or HEK-293 cells supported PTH(1-34)-dependent activation of AC.…”

“…(1)(2)(3)(4)(5)(6)(7)(8) The links between these individual signaling events and integrated tissue responses to PTH, such as the complex divergent effects of continuously versus intermittently administered exogenous PTH on net bone mass in vivo, (9) have not been clearly defined. Much effort has focused upon attempts to modulate PTHR signaling through use of PTH analogs, such as PTH or PTH , which may selectively activate one or the other of the two major PTHR signaling effectors, AC and PLC (10)(11)(12)(13)(14)(15)(16) For example, selective activation of the AC/protein kinase A (PKA) pathway by intermittently administered PTH(1-31), a putative ACselective PTHR agonist, was reported to account entirely for the anabolic response of bone in vivo, whereas hPTH(3-34), which does not activate AC but does stimulate protein kinase C (PKC) in bone cells, was inactive in vivo. (14,(16)(17)(18) Others have employed PTH to probe the involve-ment of PKC in the regulation of renal ion transporters and enzymes by PTH in rat and opposum kidney cells.…”

Chondrocyte terminal differentiation, apoptosis, and type X collagen expression are downregulated by parathyroid hormone

“…These receptors have been localized on embryonic chick and rabbit cartilage cells (Kioke et al, 1990). In chondrocytes, ligand binding of the type 1 PTH/ PTHrP common receptor (PTH1R) activates several second-messenger systems (Abou-Samra et al, 1994;Azarani et al, 1996;Suda, 1997;Serra et al, 1999). PTH has a stimulatory effect on proliferation of chondroprogenitor cells and inhibits collagen and matrix synthesis in avian epiphyseal cartilage via cAMP-dependent pathways (Pines et al, 1990).…”