Spatial bias in cAMP generation determines biological responses to PTH type 1 receptor activation

Abstract

Physiological responses to parathyroid hormone depend on the subcellular location of receptor activity.

PTH1R Actions on Bone Using the cAMP/Protein Kinase A Pathway

“…An assumption grew in currency that abaloparatide promotes bone resorption less than PTH (1–34) (teriparatide), based on claims in clinical studies of greater gain in bone mineral density and greater increase in circulating bone resorption markers ( 31 ). Those claims have been called into question, based on interpretation of bone mineral density and bone marker data ( 32 , 38 , 103 ). It has been postulated repeatedly that these claimed differences in clinical responses can be explained by different modes of interaction with PTH1R of PTH (1–34) and abaloparatide, but no evidence for causal relationship has been obtained.…”

“…Despite these similar actions of PTH (1–34) and abaloparatide, it has nevertheless been shown in another study that it is possible to modify PTH structurally to separate plasma membrane from endosomal activation. An analog of PTH prepared by epimerization of residue 7 (PTH 7d ) behaved as a biased agonist, eliciting cAMP production at the plasma membrane but not at the endosome ( 103 ). In in vivo studies in which bone formation was not measured, PTH 7d treatment had no effect on 1-hydroxylation of vitamin D, whereas a long acting PTH peptide that shows endosomal transfer and persistent cAMP effect much greater than PTH (1–34) ( 89 ), substantially increased vitamin D 1-hydroxylation and the amount of bone assessed by microcomputed tomography ( 103 ).…”

“…An analog of PTH prepared by epimerization of residue 7 (PTH 7d ) behaved as a biased agonist, eliciting cAMP production at the plasma membrane but not at the endosome ( 103 ). In in vivo studies in which bone formation was not measured, PTH 7d treatment had no effect on 1-hydroxylation of vitamin D, whereas a long acting PTH peptide that shows endosomal transfer and persistent cAMP effect much greater than PTH (1–34) ( 89 ), substantially increased vitamin D 1-hydroxylation and the amount of bone assessed by microcomputed tomography ( 103 ). This further supports a biological role for endosomal PTH action, but unfortunately whether this might contribute to either an anabolic or a resorptive effect of PTH was not addressed.…”

“…They also consider the possibility that the differences noted by others in clinical studies might be related to pharmacokinetic or other factors (102). The questions nevertheless remain (i) whether there are consistent differences in action between PTH on the one hand and either abaloparatide or the N-terminal domain of PTHrP on the other, and (ii) whether significant differences in pharmacological effects exist between PTH and abaloparatide (103). Thus although the endosomal transfer of PTH/PTH1R complex resulting in persistent endosomal cAMP generation is now well established (Figure 5), the results of Sato et al (102) call for reappraisal of the comparisons that have been made between the molecular events in response to PTH and those in response to abaloparatide.…”

Soluble cyclase-mediated nuclear cAMP synthesis is sufficient for cell proliferation

“…This temporal bias might convey informational content if cells are able to discriminate cAMP production from different sources and trigger unique biological outcomes differentially associated with these two phases. In this context, a sustained cAMP elevation was reported to be specifically required in several physiological responses, such as chronic inflammation and pain [34][35][36][37] , to resume meiosis in the oocyte 38 , and several reports indicate its role in cAMP-dependent nuclear transcription 30,31,[39][40][41][42][43] . Similarly, internalization-mediated sustained cAMP elevation can aid in producing stable responses to pulsatile or low-concentration hormones such as PTH.…”