GPCRs, RTKs, and signaling dynamics

Parathyroid Hormone Signaling: PTH regulates cell activity in its target tissues by binding to the G protein-coupled PTH1R.  In in vitro models of kidney and bone, PTH mediates a variety of responses by activating the Gαs/adenylyl cyclase (AC)- and Gαq/phospholipase C (PLC)-coupled PTH1 receptor and these responses can be mimicked by increasing intracellular cAMP, mobilizing intracellular stores of Ca2+ and by activating protein kinase C (PKC) (see the figure below).
Studies from our lab and others show that PTH also regulates long-term cellular responses like proliferation and differentiation by stimulating the local release of epidermal growth factor receptor (EGFR) ligands, a process termed EGFR transactivation.  EGFR transactivation contributes to PTH-dependent activation of Extracellular signal Regulated Kinase (ERK), but  is also mimicked by cAMP, Ca2+ and protein kinase C (PKC).  We are interested in defining the role of classic PTH second messengers in EGFR-dependent ERK activation.

We are also investigating the ability of some PTH analogs to selectively activate G protein-coupled or β-arrestin coupled signaling in PTH target tissues. PTH analogs that activate one or the other pathway are termed "biased agonists".  PTH (1-34) contains all of the biological activity of the endogenous full length peptide [PTH(1-84)] and activates G-protein  as well as β-arrestin-mediated signaling. In contrast, PTH (7-34), a PTH peptide missing the first 6 residues of PTH (1-34), does not activate AC or PLC but produces β-arrestin-dependent ERK activation.  In bone cells, PTH (7-34) produces β-arrestin-dependent and G protein-independent increases bone formation, suggesting it might prove useful in the treatment of osteoporosis.

Signaling Dynamics: In many cells, multiple receptors use the same downstream signaling pathways to regulate cellular activity.  In renal OK cells, both EGF and PTH increase activity, but the temporal and intensity of that activation is different.  In fact, timing and intensity is different between low and high doses of EGF and low and high doses of PTH (see the figure below)For example, a high dose of EGF (100 ng/ml)  rapidly increase ERK activity, and the response peaks at ~2.5 min at 5x basal.  ERK activity in response to 100 ng/ml EGF stays above basal for at least 120 min.  In contrast, the response to 0.01 ng/ml EGF peaks at 15 min at ~1.5 x basal, and then declines back to basal levels by 30 min.  In many cells these differences in the intensity as well as the onset and duration of ERK activation provide specific instructions for what cellular response to produce.