Gαq and phospholipase C-β: turn on, turn off, and do it fast
ABSTRACT Heterotrimeric G proteins and G protein-coupled receptors represent conserved protein families with origins in the prokaryotes, but the various G protein-regulated effectors are heterogeneous in structure and function. The effectors apparently evolved ways to listen to G proteins late in their evolutionary histories. The structure of a complex between the effector protein phospholipase C-β3 (PLC-β3) and its activator, Gα(q), suggests that several effectors independently evolved a structurally similar helix-turn-helix segment for G protein recognition. PLC-βs are also guanosine triphosphatase (GTPase)-activating proteins (GAPs) for the G(q) that activates them. In a second example of convergent evolution, the GAP activity of these proteins depends on a flexible asparagine-containing loop that resembles the GAP site on RGS proteins, another family of G protein GAPs. Together, these two sites are proposed to cooperate to enable fast binding to activated Gα(q), followed by fast deactivation. This cycle allows rapid sampling of the activation state of G(q)-coupled receptors while providing efficient signal transduction.
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- "Interestingly, SPHK-1-GFP fluorescence increased in egl-8/PLCb mutants, suggesting that egl-8/PLCb may negatively regulate SPHK-1 localization. PLCb has Gaq GAP activity (Ross 2011), suggesting that EGL-30/Gaq may be able to activate UNC-73/Trio in egl-8/PLCb mutants. Alternatively, EGL- 8/PLCb may compete with UNC-73/Trio for activation by EGL-30/Gaq, which may lead to an enhancement of UNC- 73/Trio signaling in the absence of egl-8/PLCb. "
ABSTRACT: Sphingolipids are potent lipid second messengers that regulate cell differentiation, migration, survival, and secretion, and alterations in sphingolipid signaling have been implicated in a variety of diseases. However, how sphingolipid levels are regulated, particularly in the nervous system, remains poorly understood. Here, we show that the generation of sphingosine-1-phosphate by sphingosine kinase (SphK) promotes neurotransmitter release. Electrophysiological, imaging, and behavioral analyses of Caenorhabditis elegans mutants lacking sphingosine kinase sphk-1 indicate that neuronal development is normal, but there is a significant defect in neurotransmitter release from neuromuscular junctions. SPHK-1 localizes to discrete, nonvesicular regions within presynaptic terminals, and this localization is critical for synaptic function. Muscarinic agonists cause a rapid increase in presynaptic SPHK-1 abundance, whereas reduction of endogenous acetylcholine production results in a rapid decrease in presynaptic SPHK-1 abundance. Muscarinic regulation of presynaptic SPHK-1 abundance is mediated by a conserved presynaptic signaling pathway composed of the muscarinic acetylcholine receptor GAR-3, the heterotrimeric G protein Gαq, and its effector, Trio RhoGEF. SPHK-1 activity is required for the effects of muscarinic signaling on synaptic transmission. This study shows that SPHK-1 promotes neurotransmitter release in vivo and identifies a novel muscarinic pathway that regulates SphK abundance at presynaptic terminals.Genes & development 05/2012; 26(10):1070-85. DOI:10.1101/gad.188003.112 · 12.64 Impact Factor
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ABSTRACT: Phospholipase Cβ2 (PLCβ2) is a large, multidomain enzyme that catalyzes the hydrolysis of the signaling lipid phosphoinositol 4,5 bisphosphate (PIP2) to promote mitogenic and proliferative changes in the cell. PLCβ2 is activated by Gα and Gβγ subunits of heterotrimeric G proteins, as well as small G proteins and specific peptides. Activation depends on the nature of the membrane surface. Recent crystal structures suggest one model of activation involving the movement of a small autoinhibitory loop upon membrane binding of the enzyme. Additionally, solution studies indicate multiple levels of activation that involve changes in the membrane orientation as well as interdomain movement. Here, we review the wealth of biochemical studies of PLCβ2-G protein activation and propose a comprehensive model that accounts for both the crystallographic and solution results.Biochimica et Biophysica Acta 08/2011; 1808(12):2940-7. DOI:10.1016/j.bbamem.2011.08.028 · 4.66 Impact Factor
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ABSTRACT: Heterotrimeric G proteins have a critical role in mediating signal transduction by ligand-stimulated GPCRs. While activation of heterotrimeric G proteins is known to proceed via the G protein guanine nucleotide cycle, there is much uncertainty regarding the process that determines efficacy, the extent of response across signaling pathways. Gα(GTP) can interact with multiple binding partners, including several effectors and regulators. Cross-talk by other receptor-signaling pathways can alter the response. It remains unclear whether G protein efficacy is regulated. This lack of clarity impairs our ability to predict and manipulate the pharmacological behavior of activated G proteins. This review will discuss emerging evidence that implicates monomeric RhoA in the process that regulates G(q) efficacy.Biochemical and Biophysical Research Communications 11/2011; 415(2):215-9. DOI:10.1016/j.bbrc.2011.10.063 · 2.28 Impact Factor