Mechanisms of homologous and heterologous desensitization of PTH/PTHrP receptor signaling in LLC-PK1 cells.
Parathyroid hormone (PTH) activates multiple intracellular effectors, including adenylyl cyclase (AC) and phospholipase C (PLC), via a single receptor [PTH/parathyroid hormone-related protein receptor (PTHR)] expressed in bone and kidney. Homologous desensitization of PTHR signaling occurs, but the relative importance of reduced receptor expression vs. 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 adenosine 3',5'-cyclic monophosphate 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.
Guo
J
J
Endocrine Unit, Massachusetts General Hospital, Boston, USA.
Liu
B Y
BY
Bringhurst
F R
FR
D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D002116:Calcitonin / Q000494:pharmacology; D015536:Down-Regulation; D018374:LLC-PK1 Cells / Q000187:drug effects / Q000378:metabolism*; D010281:Parathyroid Hormone / Q000494:pharmacology; D044168:Receptor, Parathyroid Hormone, Type 1; D018003:Receptors, Calcitonin / Q000378:metabolism; D018016:Receptors, Parathyroid Hormone / Q000502:physiology*; D015398:Signal Transduction; D013552:Swine; D010738:Type C Phospholipases / Q000378:metabolism
D010281:Parathyroid Hormone; D044168:Receptor, Parathyroid Hormone, Type 1; D018003:Receptors, Calcitonin; D018016:Receptors, Parathyroid Hormone; D002116:Calcitonin; D010738:Type C Phospholipases; D000262:Adenylyl Cyclases