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(Received for publication, January 25, 1996)
From the Departments of 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+/H+ exchanger NHE3 activity in renal cells.
This response is believed to be mediated by ligand binding to a common
receptor (i.e. PTH/PTHRP receptor type I) and activation of
cAMP-dependent and/or
Ca2+/phospholipid-dependent protein kinases
(PKA and PKC, respectively). However, the mechanism of action of these
N-terminal peptides is now unclear because of recent data reporting the
existence of additional receptor isoforms. Therefore, to directly
examine the ligand binding and signaling characteristics of the
PTH/PTHRP receptor type I and its ability to elicit a biological
response, cDNAs encoding the rat type I receptor and the rat NHE3
isoform were transfected into Chinese hamster ovary (AP-1) cells that
lack endogenous expression of these proteins. Competition binding
assays using
[125I-Tyr36]PTHRP-(, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , )-NH2
radioligand indicated that several biologically active human N-terminal
PTH and PTHRP fragments (PTH-(, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ), PTH-(, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ), PTH-(, , , , , , , , , , , , , , ),
PTH-(, , , , , , , , , , , , , , , , , , , , ), and PTHRP-(, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , )) were capable of binding to the type I
receptor. Both PTH-(, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ) and PTHRP-(, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ) stimulated adenylate
cyclase and PKC activities in these cells, whereas PTH-(, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ),
PTH-(, , , , , , , , , , , , , , ), and PTH-(, , , , , , , , , , , , , , , , , , , , ) selectively enhanced only PKC activity.
PTHRP-(, , , , , , , , , , , , , , , ), a biologically inert fragment, was incapable of binding
to this receptor and influencing either the PKA or PKC pathway.
Furthermore, all the analogues with the exception of PTHRP-(, , , , , , , , , , , , , , , )
inhibited NHE3 activity. Inhibition of PKC by the potent antagonist
chelerythrine chloride abolished the depression of NHE3 activity by
PTH-(, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ), PTH-(, , , , , , , , , , , , , , ), and PTH-(, , , , , , , , , , , , , , , , , , , , ) but did not alleviate the
effects of PTH-(, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ). Likewise, antagonism of PKA by H-89 was unable
to prevent the inhibition caused by PTH-(, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ). However, inhibition of
both PKA and PKC by the nonselective protein kinase antagonist H-7
abolished the reduction of NHE3 activity by PTH-(, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ). These data
indicate that discrete N-terminal analogues of PTH and PTHRP can
interact with the classical PTH/PTHRP receptor type I and activate PKA
and/or PKC. Activation of either signaling pathway independently leads
to inhibition of NHE3.
Volume 271, Number 25,
Issue of June 21, 1996
pp. 14931-14936
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.
§¶
,¶
and
Physiology and
¶ Medicine, McGill University and the § Calcium
Research Laboratory, Royal Victoria Hospital, Montreal H3A 1Y6,
Canada
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