Receptors & clinical investigation最新文献

G protein-coupled receptors (GPCRs) are a large family of transmembrane proteins that perceive many extracellular signals and transduce them into cellular physiological responses. GPCRs regulate immunity in both vertebrates and invertebrates. However, the mechanisms responsible for such regulation are not fully understood. Recent research using the genetically tractable model organism Caenorhabditis elegans has led to the identification of specific GPCRs, neurotransmitters, neurons and non-neural cells in the regulation of innate immunity. Several neural circuits have been demonstrated to function in GPCR-dependent immuno-regulatory pathways. Besides being essential in neural-immune interactions, GPCRs also regulate innate immune response in non-neural tissues cell-autonomously through mechanisms independent of neural circuits. Here we review GPCR-mediated neural control of innate immunity in C. elegans and briefly discuss GPCR-dependent immune regulation via non-neural mechanisms.

The human immunodeficiency virus type 1 (HIV-1) envelope glycoproteins (Env) mediate viral entry and are the sole target of neutralizing antibodies. Recent studies show that the metastable HIV-1 Env trimer can transit among three conformational states: State 1, State 3, and State 2, corresponding to the "closed", "open" and intermediate conformations, respectively. During virus entry, binding to the CD4 receptor drives Env from state 1 to state 3. In the unliganded Env, transitions from the closed (State 1) conformation are restrained by intramolecular interactions among different Env residues, which regulate HIV-1 Env conformation. Releasing the specific restraints on State 1 Env leads to increased occupancy of State 2, which is a functional conformation on the entry pathway and an obligate intermediate between State 1 and State 3. Frequent sampling of intermediate State 2 allows HIV-1 to infect cells expressing low levels of CD4, and leads to resistance to several broadly neutralizing antibodies as well as small-molecule inhibitors. Recent findings provide new mechanistic insights into the function and inhibition of HIV-1 Env and will contribute to the development of new therapeutic and prophylactic interventions to combat HIV-1.

Despite the fact that ischemic stroke has been considered a leading cause of mortality in the world, recent advances in our understanding of the pathophysiological mechanisms underlying the ischemic injury and the treatment of acute ischemic stroke patients have led to a sharp decrease in the number of stroke deaths. However, this decrease in stroke mortality has also led to an increase in the number of patients that survive the acute ischemic injury with different degrees of disability. Unfortunately, to this date we do not have an effective therapeutic strategy to promote neurological recovery in these growing population of stroke survivors. Cerebral ischemia not only causes the destruction of a large number of axons and synapses but also activates endogenous mechanisms that promote the recovery of those neurons that survive its harmful effects. Here we review experimental evidence indicating that one of these mechanisms of repair is the binding of the serine proteinase urokinase-type plasminogen activator (uPA) to its receptor (uPAR) in the growth cones of injured axons. Indeed, the binding of uPA to uPAR in the periphery of growth cones of injured axons induces the recruitment of β1-integrin to the plasma membrane, β1-integrin-mediated activation of the small Rho GTPase Rac1, and Rac1-induced axonal regeneration. Furthermore, we found that this process is modulated by the low density lipoprotein receptor-related protein (LRP1). The data reviewed here indicate that the uPA-uPAR-LRP1 system is a potential target for the development of therapeutic strategies to promote neurological recovery in acute ischemic stroke patients.

Formation of the costimulatory axis between the B7-2 and CD28 coreceptors is critical for T-cell activation. Superantigens, Gram-positive bacterial virulence factors, cause toxic shock and sepsis by hyperinducing inflammatory cytokines. We report a novel role for costimulatory receptors CD28 and B7-2 as obligatory receptors for superantigens, rendering them therapeutic targets. We show that by engaging not only CD28 but also its coligand B7-2 directly, superantigens potently enhance the interaction between B7-2 and CD28, inducing thereby T-cell hyperactivation. Using a conserved twelve amino-acid domain, superantigens engage both B7-2 and CD28 at their homodimer interfaces, sites far removed from where these receptors interact, implying that inflammatory signaling can be controlled through the receptor homodimer interfaces. Short B7-2 and CD28 dimer interface mimetic peptides bind diverse superantigens, prevent superantigen binding to cell-surface B7-2 or CD28, attenuate inflammatory cytokine overexpression, and protect mice from lethal superantigen challenge. Thus, superantigens induce a cytokine storm by mediating not only the interaction between MHC-II molecule and T-cell receptor but critically, by promoting B7-2/CD28 coreceptor engagement, forcing the principal costimulatory axis to signal excessively. Our findings highlight the B7/CD28 interaction as a bottleneck in signaling for expression of inflammatory cytokines. B7-2 and CD28 homodimer interface mimetic peptides prevent superantigen lethality by blocking the superantigen-host costimulatory receptor interaction.

The bone remodeling and homeostasis are mainly controlled by the receptor-activator of nuclear factor kB (RANK), its ligand RANKL, and the soluble decoy receptor osteoprotegerin (OPG) pathway. While there is a strong association between osteoporosis and skeletal muscle dysfunction, the functional relevance of a particular biological pathway that synchronously regulates bone and skeletal muscle physiopathology remains elusive. Our recent article published in the American Journal of Physiology (Cell Physiology) showed that RANK is also expressed in fully differentiated C2C12 myotubes and skeletal muscles. We used the Cre-Lox approach to inactivate muscle RANK (RANK^mko) and showed that RANK deletion preserves the force of denervated fast-twitch EDL muscles. However, RANK deletion had no positive impact on slow-twitch Sol muscles. In addition, denervating RANK^mko EDL muscles induced an increase in the total calcium concentration ([Ca_T]), which was associated with a surprising decrease in SERCA activity. Interestingly, the levels of STIM-1, which mediates Ca²⁺ influx following the depletion of SR Ca²⁺ stores, were markedly higher in denervated RANK^mko EDL muscles. We speculated that extracellular Ca²⁺ influx mediated by STIM-1 may be important for the increase in [Ca_T] and the gain of force in denervated RANK^mko EDL muscles. Overall, these findings showed for the first time that the RANKL/RANK interaction plays a role in denervation-induced muscle atrophy and dysfunction.

G protein-coupled receptor kinases (GRKs) are a family of serine/threonine protein kinases that terminate G protein-coupled receptor (GPCR) signaling by phosphorylating the receptor and inducing its internalization. In addition to their canonical function, some GRKs can phosphorylate non-GPCR substrates and regulate GPCR signaling in a kinase-independent manner. GPCRs are abundantly expressed in the suprachiasmatic nucleus (SCN), a structure in the mammalian brain that serves as the central circadian pacemaker. Various facets of circadian timekeeping are under the influence of GPCR signaling, and thus are potential targets for GRK regulation. Despite this, little attention has been given to the role of GRKs in circadian rhythms. In this research highlight, we discuss our latest findings on the functional involvement of GRK2 in mammalian circadian timekeeping in the SCN. Using grk2 knockout mice, we demonstrate that GRK2 is critical for maintaining proper clock speed and ensuring that the clock is appropriately synchronized to environmental light cycles. Although grk2 deficiency expectedly alters the expression of a key GPCR in the SCN, our study also reveals that GRK2 has a more direct function that touches the heart of the circadian clock.