Purinergic Receptors Crosstalk with CCR5 to Amplify Ca 2+ Signaling
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ORIGINAL RESEARCH
Purinergic Receptors Crosstalk with CCR5 to Amplify Ca2+ Signaling Mizuho Horioka1,2 · Emilie Ceraudo2 · Emily Lorenzen2 · Thomas P. Sakmar2 · Thomas Huber2 Received: 5 June 2020 / Accepted: 6 November 2020 © The Author(s) 2020
Abstract Many G protein-coupled receptors (GPCRs) signal through more than one subtype of heterotrimeric G proteins. For example, the C–C chemokine receptor type 5 (CCR5), which serves as a co-receptor to facilitate cellular entry of human immunodeficiency virus 1 (HIV-1), normally signals through the heterotrimeric G protein, Gi. However, CCR5 also exhibits G protein signaling bias and certain chemokine analogs can cause a switch to Gq pathways to induce Ca2+ signaling. We want to understand how much of the C a2+ signaling from Gi-coupled receptors is due to G protein promiscuity and how much is due to transactivation and crosstalk with other receptors. We propose a possible mechanism underlying the apparent switching between different G protein signaling pathways. We show that chemokine-mediated Ca2+ flux in HEK293T cells expressing CCR5 can be primed and enhanced by ATP pretreatment. In addition, agonist-dependent lysosomal exocytosis results in the release of ATP to the extracellular milieu, which amplifies cellular signaling networks. ATP is quickly degraded via ADP and AMP to adenosine. ATP, ADP and adenosine activate different cell surface purinergic receptors. Endogenous Gqcoupled purinergic P2Y receptors amplify Ca2+ signaling and allow for Gi- and Gq-coupled receptor signaling pathways to converge. Associated secretory release of GPCR ligands, such as chemokines, opioids, and monoamines, should also lead to concomitant release of ATP with a synergistic effect on C a2+ signaling. Our results suggest that crosstalk between ATP-activated purinergic receptors and other Gi-coupled GPCRs is an important cooperative mechanism to amplify the intracellular Ca2+ signaling response. Keywords GPCR signaling · CCR5 · Chemokines · Purinergic receptors · G protein bias · Crosstalk
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10571-020-01002-1) contains supplementary material, which is available to authorized users. * Thomas P. Sakmar [email protected] * Thomas Huber [email protected] Mizuho Horioka [email protected] Emilie Ceraudo [email protected] Emily Lorenzen [email protected] 1
Tri-Institutional Program in Chemical Biology, New York, NY 10065, USA
Laboratory of Chemical Biology and Signal Transduction, The Rockefeller University, 1230 York Ave., New York, NY, USA
2
Introduction G protein-coupled receptors (GPCRs) are the largest family of transmembrane receptors that mediate many important physiological processes. They are activated by ligand binding on the extracellular side and then couple preferentially to a unique Gα protein sub-family on the intracellular side to activate specific downstream signaling pathways. The Gα subunit in comp
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