Thermodynamics of GPCR activation

G-protein coupled receptors (GPCRs) are the largest family of signaling proteins that are responsible for information input from the extracellular environment. The plasma membrane in which GPCRs reside usually carries an electrostatic membrane potential (ΔΨ). This potential and its variations in some cell types are important for cellular functions, including GPCR signaling (Mahaut-Smith et al. 2008; Zhang et al. 2014). The phenomenon of membrane potential-sensitivity signaling has been observed in many GPCRs, including the M2 receptor (Ben-Chaim et al. 2003), P2Y1 (Gurung et al. 2008), the α2A-adrenoceptor (Rinne et al. 2013), the β1-adrenoceptor (Birk et al. 2015), the dopamine D2 receptor (Sahlholm et al. 2008), and the histamine H3 receptor (Sahlholm et al. 2012). The signaling capacity of a GPCR changes when the membrane potential is experimentally modulated. A question often raised is what and where is the voltage sensor? Researchers would like to know which amino acid residue(s) in the GPCR molecule is responsible for ΔΨ-sensitivity. In general, a particular ligand-GPCR pair can be considered as a unique system that has different thermodynamic parameters and pharmacological properties from other ligand-GPCR combinations (Masuho et al. 2015). In real in vivo situations, such systems are necessarily coupled with each other and with upstream and downstream networks, and their thermodynamic parameters can be influenced strongly by the environment, including ΔΨ. In the following report, we will first discuss the thermodynamics of an isolated GPCR activation process according to the classical view of ligand-receptor equilibrium, and then attempt to address the above questions about ΔΨ-sensitivity.