A new light on PLCβ!

In this issue of Cell Chemical Biology, Kim et al. present a novel optogenetic tool, opto-PLCβ, to control PLCβ signaling optically. In addition to eliciting PIP2 hydrolysis and downstream signaling in cells, opto-PLCβ also enabled probing the impact of PLCβ signaling on amygdala synaptic plasticity and fear learning in mice.

Optical control of cell-surface and endomembrane-exclusive β-adrenergic receptor signaling.

Beta-adrenergic receptors (βARs) are G protein-coupled receptors (GPCRs) that mediate catecholamine hormone-induced stress responses, such as elevation of heart rate. Besides those that are plasma membrane-bound, endomembrane βARs are also signaling competent. Dysregulation of βAR pathways underlies severe pathological conditions.

AGS3-based optogenetic GDI induces GPCR-independent Gβγ signaling and macrophage migration.

G protein-coupled receptors (GPCRs) are efficient Guanine nucleotide exchange factors (GEFs) and exchange GDP to GTP on the Gα subunit of G protein heterotrimers in response to various extracellular stimuli, including neurotransmitters and light. GPCRs primarily broadcast signals through activated G proteins, GαGTP, and free Gβγ, and are major disease drivers. Evidence shows that the ambient low threshold signaling required for cells is likely supplemented by signaling regulators such as non-GPCR GEFs and Guanine nucleotide Dissociation Inhibitors (GDIs).

Optical Control of Cell-Surface and Endomembrane-Exclusive β-Adrenergic Receptor Signaling.

Beta-adrenergic receptors (βARs) are G protein-coupled receptors (GPCRs) that mediate catecholamine-induced stress responses, such as heart rate increase and bronchodilation. In addition to signals from the cell surface, βARs also broadcast non-canonical signaling activities from the cell interior membranes (endomembranes). Dysregulation of these receptor pathways underlies severe pathological conditions.

Spatiotemporal Optical Control of Gαq-PLCβ Interactions.

Cells experience time-varying and spatially heterogeneous chemokine signals , activating cell surface proteins including G protein-coupled receptors (GPCRs). The Gαq pathway activation by GPCRs is a major signaling axis with broad physiological and pathological significance. Compared with other Gα members, GαqGTP activates many crucial effectors, including PLCβ (Phospholipase Cβ) and Rho GEFs (Rho guanine nucleotide exchange factors).

Spatiotemporal optical control of Gαq-PLCβ interactions.

Cells experience time-varying and spatially heterogeneous chemokine signals in vivo, activating cell surface proteins, including G protein-coupled receptors (GPCRs). The Gαq pathway activation by GPCRs is a major signaling axis with a broad physiological and pathological significance. Compared to other Gα members, GαqGTP activates many crucial effectors, including PLCβ (Phospholipase Cβ) and Rho GEFs (Rho guanine nucleotide exchange factors).

Molecular regulation of PLCβ signaling.

Phospholipase C (PLC) enzymes convert the membrane phospholipid phosphatidylinositol-4,5-bisphosphate (PIP2) into inositol-1,4,5-triphosphate (IP3) and diacylglycerol (DAG). IP3 and DAG regulate numerous downstream pathways, eliciting diverse and profound cellular changes and physiological responses. In the six PLC subfamilies in higher eukaryotes, PLCβ is intensively studied due to its prominent role in regulating crucial cellular events underlying many processes including cardiovascular and neuronal signaling, and associated pathological conditions.

The spatial distribution of GPCR and Gβγ activity across a cell dictates PIP3 dynamics.

Phosphatidylinositol (3,4,5) trisphosphate (PIP3) is a plasma membrane-bound signaling phospholipid involved in many cellular signaling pathways that control crucial cellular processes and behaviors, including cytoskeleton remodeling, metabolism, chemotaxis, and apoptosis. Therefore, defective PIP3 signaling is implicated in various diseases, including cancer, diabetes, obesity, and cardiovascular diseases. Upon activation by G protein-coupled receptors (GPCRs) or receptor tyrosine kinases (RTKs), phosphoinositide-3-kinases (PI3Ks) phosphorylate phosphatidylinositol (4,5) bisphosphate (PIP2), generating PIP3.

Dissociation of the G protein βγ from the Gq-PLCβ complex partially attenuates PIP2 hydrolysis.

Phospholipase C β (PLCβ), which is activated by the Gq family of heterotrimeric G proteins, hydrolyzes the inner membrane lipid phosphatidylinositol 4,5-bisphosphate (PIP2), generating diacylglycerol and inositol 1,4,5-triphosphate (IP3). Because Gq and PLCβ regulate many crucial cellular processes and have been identified as major disease drivers, activation and termination of PLCβ signaling by the Gαq subunit have been extensively studied. Gq-coupled receptor activation induces intense and transient PIP2 hydrolysis, which subsequently recovers to a low-intensity steady-state equilibrium.

Subtype-dependent regulation of Gβγ signalling.

G protein-coupled receptors (GPCRs) transmit information to the cell interior by transducing external signals to heterotrimeric G protein subunits, Gα and Gβγ subunits, localized on the inner leaflet of the plasma membrane. Though the initial focus was mainly on Gα-mediated events, Gβγ subunits were later identified as major contributors to GPCR-G protein signalling. A broad functional array of Gβγ signalling has recently been attributed to Gβ and Gγ subtype diversity, comprising 5 Gβ and 12 Gγ subtypes, respectively.