Cell surface receptors transmit biochemical signals from the extracellular space to the intracellular space by changing their conformation. This process usually includes the steps of encoding, transmission, decoding, and erasing of information (In biochemistry, information is often converted between multiple forms. This process is also called signal transduction, which differs from using electrons as the carrier of information from one place to another along a metal wire. Such process is usually referred to as signal transmission.). A reliable transduction usually depends on a signaling pathway driven by free energy. As the largest receptor protein family in eukaryotic cells, G protein-coupled receptors (GPCRs) interact with a wide variety of ligands, but the homology of their amino acid sequences suggests that they most likely share common signal transduction and energy-coupling mechanisms. What is the 3D structural basis of such common mechanisms? What mechanistic/functional role does the membrane potential and other electrostatic interactions play during GPCR activation? This chapter focuses on the common structural characteristics and possible common activation mechanisms of class-A GPCR signal transduction proteins and explores the key incentive role of “proton transfer” for GPCR activation under the regulation of membrane potential.