Competing G protein‐coupled receptor kinases balance G protein and β‐arrestin signaling

Abstract

The molecular mechanisms and hidden dynamics governing ERK activation by the angiotensin II type 1A receptor are studied and deciphered, revealing a signal balancing mechanism that is found to be relevant to a range of other seven transmembrane receptors.

Arginine Vasopressin Enhances Cell Survival via a G Protein–Coupled Receptor Kinase 2/β-Arrestin1/Extracellular-Regulated Kinase 1/2–Dependent Pathway in H9c2 Cells

“…b-Arrestins are recruited to GRK-phosphorylated GPCR to induce a number of cellular processes, including persistent ERK1/2 activation, and have been shown to promote cardiac protection under conditions of stress (Luttrell et al, 2001;Noma et al, 2007;Kim et al, 2012). Thus, we sought to determine whether b-arrestins are required for the V 1A R/ GRK2-dependent effects on ERK1/2 and survival signaling.…”

“…GRKs were initially identified as desensitizing regulators of GPCR, terminating their acute signaling responses to agonist stimulation via phosphorylation of the C-terminal tail of the receptor (Benovic et al, 1986;Hausdorff et al, 1990). It has since been clearly demonstrated that beyond desensitization, GRK also initiates G protein-independent signaling events that act to regulate ERK1/2 activity, for instance, via the recruitment of the scaffolding proteins b-arrestins through differential phosphorylation of GPCRs (Heitzler et al, 2012). These events commonly promote more persistent ERK1/2 activity than that mediated by G proteins, and have been demonstrated to impact numerous cellular processes, including regulation of apoptosis and cell survival in numerous cells and, importantly, in the heart (Dorn, 2009;Tilley, 2011;Huang et al, 2011).…”

“…The GRKs can also alter cellular physiology independent of PKC through phosphorylation-dependent recruitment of b-arrestins and subsequent activation of downstream pathways, including extracellular-regulated kinase 1/2 (ERK1/2) signaling, which can act to inhibit the ubiquitous responses to cell stress including apoptosis (Dorn, 2009;Huang et al, 2011;Tilley, 2011). Indeed, in the heart, G protein-independent signaling has been shown to promote cardioprotection downstream of angiotensin II-and b-adrenergic receptor activation during conditions of myocardial stress (Noma et al, 2007;Kim et al, 2012). These findings led to the development of biased ligands, GPCR antagonists that activate unique G protein-independent pathways.…”

Cells as Machines: Towards Deciphering Biochemical Programs in the Cell

“…On a quantitative model of the cell cycle [48], Figure 5 depicts the landscape of the satisfaction degree of an oscillation property with amplitude constraint, as a function of two parameters of the model. The landscape is iteratively sampled by CMA-ES to find a path towards satisfaction, and optimize the model parameter values, for instance going from k 2 to k for fitting models to experimental data in high dimension (up to 100 parameters), revisiting the structure of the reaction network in case of failure, making new biological hypotheses based on simulation, and verifying them by new experiments, for instance for deciphering the complex dynamics of a cell signaling network in [23]. The same strategy for parameter optimization can also be used to compute control parameters to achieve a desired behavior at the single cell of cell population levels.…”

Trace Simplifications Preserving Temporal Logic Formulae with Case Study in a Coupled Model of the Cell Cycle and the Circadian Clock

“…When numerical values for model parameters can be found to fit the data, the model can be used to make predictions, whereas the absence of any good fit may suggest to revisit the structure of the model and gain new insights in the biology of the system, see for instance [23,15].…”