G(alpha)S-to-G(alpha)i switch of G protein-coupled receptor signalling in arthritis

• Applicant: Professor Dr. Rainer H. Straub
• Subject Area: Rheumatology
• Term: from 2017 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 355701977

Research in molecular cardiology and pneumology has identified an important desensitization mechanism of the Beta1/2 adrenergic receptor (also pertinent for other receptors of similar type), which is relevant in clinical medicine (heart failure, asthma). The desensitization switches canonical GalphaS signaling with increased intracellular cyclic AMP (cAMP) to Galphai signaling with low cAMP and MAP kinase activation. Phosphodiesterase inhibitors like apremilast, rolipram, or roflumilast do not work when the switch has happened. This switch was not studied in the context of immunology in rheumatic diseases, although apremilast is already in use. A similar switch seems to happen in rheumatoid arthritis (RA, our target disease), and the outcome is a proinflammatory event, which can be the important reason why apremilast does not work (shown in RA). Our preliminary results in RA clearly demonstrate signs of the switch as a proinflammatory event with increased TNF.This project will address time and proinflammatory consequence of the switch in humans already before outbreak of RA, in early RA, and late RA (time course and cell types); it will investigate the switch at different time points and in different cell types during the manifestation of collagen type II-induced arthritis (CIA) in mice; it will study the strong influence of hypoxia making use of HIF-1alpha modulators and studying the crosstalk with proteinkinase A and Erk1/2; it will scrutinize how the switch can be reverted in RA synovial cells, and whether reversion has anti-inflammatory consequences in RA synovial cells. The animal model is used in order to compare the situation in RA with CIA to define potential differences of involved pathways. These project will go beyond our preliminary work in order to demonstrate the full picture of the proinflammatory GalphaS - to - Galphai switch in RA and CIA.

• DFG Programme: Research Grants