Mechanisms of homologous and heterologous desensitization of pth/
pthrp receptor signaling in llc-pk1 cells.
Guo, Jun, Bu-Yuan Liu, and F. Richard Bringhurst.
Endocrine Unit, Massachusetts General Hospital and Harvard Medical
School
APStracts 4:0098E, 1997.
Parathyroid hormone (PTH) activates multiple intracellular effectors,
including adenylyl cyclase (AC) and phospholipase C (PLC), via a
single receptor (PTHR) expressed in bone and kidney. Homologous
desensitization of PTHR signaling occurs, but the relative importance
of reduced receptor expression versus impaired receptor-effector
coupling in this process remains unclear. It also is not known if AC
and PLC responses to PTH are desensitized independently or
interdependently. In LLC-PK1 cells that expressed transfected wild
-type PTHRs, PTH caused dose- and time-dependent desensitization of
both the AC and PLC responses to PTH without altering PTHR
expression. Desensitization of AC was blocked in mutant cells
resistant to cAMP but not when cells expressed mutant PTHRs with
defective PLC coupling. Desensitization of PLC was unaffected by PKA
blockade, partially mimicked by phorbol ester and not reproduced by
agents that selectively activated AC.
The finding that homologous PTHR desensitization in LLC-PK1 cells is
signal-specific suggests that prior exposure of other cells to PTH
also may induce discordant regulation of subsequent PTHR signaling,
altering the character, as well as the intensity, of the hormonal
response.
Received 3 September 1996; accepted in final form 2 April 1997.
APS Manuscript Number E439-6.
Article publication pending Am. J. Physiol. (Endocrinol. Metab.).
ISSN 1080-4757 Copyright 1997 The American Physiological Society.
Published in APStracts on 13 May 1997