Preface: Changing Paradigms for G-Protein–Coupled Receptor Signaling
Apart from the classical activation of G-proteins after ligand binding, GPCRs are able to recruit epidermal growth factor receptor (EGFR) as a downstream signaling partner in mediating signals. This phenomenon of co-opting and activating a receptor tyrosine kinase for enhancing downstream signals after GPCR stimulation represents transactivation. Increasing evidence shows that transactivation of EGFR can be mediated by many GPCRs, indicating that this mechanism could be integral in providing diversity to downstream signaling. Although studies show that transactivation could play a beneficial role in cardiac hypertrophic responses, more studies are required to detail the effects of EGFR activation. In this context, the review by Grisanti et al, on “Cardiac-GPCR-mediated EGFR transactivation: Impact and therapeutic implications” provides an in-depth discussion on the current understanding of EGFR transactivation with a focus on angiotensin II, urotensin II, and β-adrenergic receptors systems. This in-depth article is followed by a comprehensive review on the mechanistic underpinnings on transactivation process. A quintessential step in the process of transactivation involves generation of the agonist to activate receptor tyrosine kinase after GPCR stimulation. A key step involves activation of extracellular proteases that cleave and release agonists for transactivation. The review by Schafer and Blaxall on “G protein coupled receptor-mediated transactivation of extracellular proteases” discusses the activation of extracellular proteases such as A Disintegrin and Metalloproteases and matrix metalloproteinases after GPCR stimulation. Studies show that activation of extracellular proteases provides for increasing the diversity and reach of signals initiated after GPCR stimulation including activation of EGFRs, transforming growth factor β receptor, or protease-activated receptors. These 2 reviews encompass insightful discussion on the activation of unique yet myriad of downstream signals in addition to canonically activated G-protein–dependent pathways.
Traditionally, it is believed that GPCR activation leads to termination of the signals by desensitization mediated by phosphorylation through kinases (GRKs, PKA, and PKC). GPCR phosphorylation (mediated by GRKs, PKA, and PKC) that occurs in response to its cognate agonist is termed as homologous desensitization, whereas heterologous desensitization happens by indiscriminate phosphorylation (mediated by PKA and PKC) of stimulated and unstimulated GPCRs.