Physiological Temperature Changes Fine-Tune beta(2)-Adrenergic Receptor-Induced Cytosolic cAMP Accumulation

Faro, Dennis; Boekhoff, Ingrid; Gudermann, Thomas und Breit, Andreas (2021): Physiological Temperature Changes Fine-Tune beta(2)-Adrenergic Receptor-Induced Cytosolic cAMP Accumulation. In: Molecular Pharmacology, Bd. 100, Nr. 3: S. 203-216

Abstract

Norepinephrine (NE) controls many vital body functions by activating adrenergic receptors (ARs). Average core body temperature (CBT) in mice is 37 degrees C. Of note, CBT fluctuates between 36 and 38 degrees C within 24 hours, but little is known about the effects of CBT changes on the pharmacodynamics of NE. Here, we used Peltier element-controlled incubators and challenged murine hypothalamic mHypoA -2/10 cells with temperature changes of +/- 1 degrees C. We observed enhanced NE-induced activation of a cAMP-dependent luciferase reporter at 36 compared with 38 degrees C. mRNA analysis and subtype specific antagonists revealed that NE activates beta(2)- and beta(3)-AR in nnHypoA-2/10 cells. Agonist binding to the beta(2)-AR was temperature insensitive, but measurements of cytosolic cAMP accumulation revealed an increase in efficacy of 45% +/- 27% for NE and of 62% +/- 33% for the beta(2)-AR-selective agonist salmeterol at 36 degrees C. When monitoring NE-promoted cAMP efflux, we observed an increase in the absolute efflux at 36 degrees C. However, the ratio of exported to cytosolic accumulated cAMP is higher at 38 degrees C. We also stimulated cells with NE at 37 degrees C and measured cAMP degradation at 36 and 38 degrees C afterward. We observed increased cAMP degradation at 38 degrees C, indicating enhanced phosphodiesterase activity at higher temperatures. In line with these data, NE-induced activation of the thyreoliberin promoter was found to be enhanced at 36 degrees C. Overall, we show that physiologic temperature changes fine-tune NE-induced cAMP signaling in hypothalamic cells via beta(2)-AR by modulating cAMP degradation and the ratio of intra-and extracellular cAMP. SIGNIFICANCE STATEMENT Increasing cytosolic cAMP levels by activation of G protein-coupled receptors (GPCR) such as the beta(2)-adrenergic receptor (AR) is essential for many body functions. Changes in core body temperature are fundamental and universal factors of mammalian life. This study provides the first data linking physiologically relevant temperature fluctuations to beta(2)-AR-induced cAMP signaling, highlighting a so far unappreciated role of body temperature as a modulator of the prototypic class A GPCR.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 0026-895X
• Sprache: Englisch