Lysophosphatidylcholine is associated with neurodegeneration and demyelination. Freeman et al. demonstrate that lysophosphatidylcholine triggers NLRP3- and NLRC4-dependent inflammasome activation, and in a synergistic fashion, NLRP3 and NLRC4 contribute to a cuprizone-induced demyelination model in vivo.

The inflammasome is a large macromolecular complex that contains multiple copies of a receptor or sensor of pathogenderived or damage-derived molecular patterns, pro-caspase-1, and an adaptor called ASC (apoptotic speck containing protein with a CARD), which results in caspase-1 maturation. Caspase-1 then mediates the release of pro-inflammatory cytokines such as IL-1b and IL-18. These cytokines play critical roles in mediating immune responses during inflammation and innate immunity. Broader studies of the inflammasome over the years have implicated their roles in the pathogenesis of a variety of inflammatory diseases. Recently, studies have shown that the inflammasome modulates neuroinflammatory cells and the initial stages of neuroinflammation. A secondary cascade of events associated with neuroinflammation (such as oxidative stress) has been shown to activate the inflammasome, making the inflammasome a promising therapeutic target in the modulation of neurodegenerative diseases. This review will focus on the pathogenic role that inflammasomes play in neurologic diseases such as Alzheimer's disease, traumatic brain injury, and multiple sclerosis.

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Heterotrimeric guanine nucleotide-binding proteins (G proteins) transmit signals from membrane bound G protein-coupled receptors (GPCRs) to intracellular effector proteins. The G q subfamily of G␣ subunits couples GPCR activation to the enzymatic activity of phospholipase C-␤ (PLC-␤). Regulators of G protein signaling (RGS) proteins bind to activated G␣ subunits, including G␣ q , and regulate G␣ signaling by acting as GTPase activating proteins (GAPs), increasing the rate of the intrinsic GTPase activity, or by acting as effector antagonists for G␣ subunits. GPCR kinases (GRKs) phosphorylate agonist-bound receptors in the first step of receptor desensitization. The amino termini of all GRKs contain an RGS homology (RH) domain, and binding of the GRK2 RH domain to G␣ q attenuates PLC-␤ activity. The RH domain of GRK2 interacts with G␣ q/11 through a novel G␣ binding surface termed the "C" site. Here, molecular modeling of the G␣ q ⅐GRK2 complex and site-directed mutagenesis of G␣ q were used to identify residues in G␣ q that interact with GRK2. The model identifies Pro 185 in Switch I of G␣ q as being at the crux of the interface, and mutation of this residue to lysine disrupts G␣ q binding to the GRK2-RH domain. Switch III also appears to play a role in GRK2 binding because the mutations G␣ q -V240A, G␣ q -D243A, both residues within Switch III, and G␣ q -Q152A, a residue that structurally supports Switch III, are defective in binding GRK2. Furthermore, GRK2-mediated inhibition of G␣ q -Q152A-R183C-stimulated inositol phosphate release is reduced in comparison to G␣ q -R183C. Interestingly, the model also predicts that residues in the helical domain of G␣ q interact with GRK2. In fact, the mutants G␣ q -K77A, G␣ q -L78D, G␣ q -Q81A, and G␣ q -R92A have reduced binding to the GRK2-RH domain. Finally, although the mutant G␣ q -T187K has greatly reduced binding to RGS2 and RGS4, it has little to no effect on binding to GRK2. Thus the RH domain A and C sites for G␣ q interaction rely on contacts with distinct regions and different Switch I residues in G␣ q .G protein-coupled receptors (GPCRs) 1 are heptahelical integral membrane proteins responsible for the transmission of extracellular signals, such as light, neurotransmitters, and hormones, to intracellular signaling pathways. Agonist-bound GPCRs directly interact with heterotrimeric (␣␤␥) G proteins and catalyze nucleotide exchange on G␣ subunits (1). Several mechanisms are in place to ensure the appropriate level of response to an agonist. Receptors become desensitized to agonist stimulation upon phosphorylation by GPCR kinases (GRKs) and subsequent binding of arrestins (2-5). The G␣ subunit has intrinsic GTPase activity that returns the G protein to the inactive GDP-bound state, promoting re-association with G␤␥ (6).A third mechanism, which accounts for the rapid desensitization observed in cellular signaling systems such as phototransduction in the eye (7), is attributed to GTPase-activating proteins (GAPs), which bind G␣ subunits and accelerate the GTPase rea...

Attending the now virtual meetings of the Association of State and Territorial Health Officials (ASTHO) alumni society facilitates seeing old friends and meeting new members. However, attendance at the alumni society also signifies that someone is a former state or territorial health official (STHO). Often, membership in the ASTHO alumni society has occurred as a planned resignation (eg, retirement, new job offer), but recent experiences suggest a trend of health officials at the state, territorial, and local levels stepping down or being involuntarily removed. [1][2][3][4]