Review

Regulation of neurotransmitter receptor desensitization by protein phosphorylation

Propofol is widely used for general anesthesia and sedation; however, the mechanisms of its anesthetic and adverse effects are not fully understood. We have previously shown that propofol activates protein kinase C (PKC) and induces its translocation in a subtype-specific manner. The purpose of this study was to identify the PKC domains involved in propofol-induced PKC translocation. The regulatory domains of PKC consist of C1 and C2 domains, and the C1 domain is subdivided into the C1A and C1B subdomains. Mutant PKCα and PKCδ with each domain deleted were fused with green fluorescent protein (GFP) and expressed in HeLa cells. Propofol-induced PKC translocation was observed by time-lapse imaging using a fluorescence microscope. The results showed that persistent propofol-induced PKC translocation to the plasma membrane was abolished by the deletion of both C1 and C2 domains in PKCα and by the deletion of the C1B domain in PKCδ. Therefore, propofol-induced PKC translocation involves the C1 and C2 domains of PKCα and the C1B domain of PKCδ. We also found that treatment with calphostin C, a C1 domain inhibitor, abolished propofol-induced PKCδ translocation. In addition, calphostin C inhibited the propofol-induced phosphorylation of endothelial nitric oxide synthase (eNOS). These results suggest that it may be possible to modulate the exertion of propofol effects by regulating the PKC domains involved in propofol-induced PKC translocation.

The modulation of the postsynaptic signaling machinery by protein phosphorylation has attracted much interest since it is key for the understanding of the regulation of a variety of synaptic functions. While advances in mass spectrometry have allowed us to begin performing large-scale analysis of protein phosphorylation in components of the PSD, the systematic collection of datasets and their functional significance within the context of regulatory signaling networks is in its infancy.

Here, we will focus on the composition of the PSD phosphoproteome describing kinase, phosphatase, and protein domain modules involved in the regulation of phosphorylation signaling. We will discuss the impact of synaptic plasticity mechanisms such as long-term potentiation (LTP) in mammalian kinomes and describe the general rules of signaling organization in the PSD phosphoproteome.

The autonomic nervous system (ANS) plays an important role in the initiation and maintenance of atrial fibrillation (AF), and modulation of the ANS function may contribute to AF control.

Anesthetized dogs received either sham treatment (SHAM group, n = 8) or low-level carotid baroreceptor stimulation (LL-CBS) treatment (LL-CBS group, n = 8). The stimulation voltage was set at 80% below the threshold. To simulate focal AF, high-frequency stimulation (HFS) was applied to local nerves during the atrial refractory period. Multielectrode catheters were attached to the atria and all the pulmonary veins to determine the changes in the AF threshold (AF-TH), the atrial effective refractory period (AERP), and the window of vulnerability (WOV) during HFS in both groups. Microelectrodes were inserted into the anterior right ganglionated plexus (ARGP) to record neural firing.

HFS induced sinus rate (SR) slowing in the superior left ganglionated plexus (SLGP). LL-CBS induced a progressive increase in AF-TH and AERP at all sites and a significant decrease in the sum of WOV at 2 hours (all P < 0.05). LL-CBS inhibited the ability of SLGP stimulation to slow the SR and the mean values of frequency and amplitude of ARGP neural activity compared with the SHAM group (all P < 0.05).

LL-CBS suppressed AF inducibility by inhibiting the neural activity of ganglionated plexuses. LL-CBS may serve as a novel therapeutic modality to treat AF.

Le système nerveux autonome (SNA) joue un rôle important dans l'apparition et le maintien de la fibrillation auriculaire (FA), et la modulation du fonctionnement du SNA peut contribuer à la maîtrise de la FA.

Des chiens anesthésiés ont reçu soit le traitement fictif (groupe de traitement fictif, n = 8) ou le traitement par stimulation de bas niveau des barorécepteurs carotidiens (LL-CBS; groupe de LL-CBS, n = 8). La tension électrique de la stimulation était réglée à 80 % en dessous du seuil. Pour stimuler la FA focale, la stimulation à haute fréquence (SHF) était appliquée aux nerfs locaux durant la période réfractaire des oreillettes. Des cathéters à multiélectrodes ont été attachés aux oreillettes et à toutes les veines pulmonaires pour déterminer les changements dans le seuil de la FA (S-FA), la période réfractaire efficace des oreillettes (PREO) et la fenêtre de vulnérabilité (FV) durant la SHF dans les 2 groupes. Des multiélectrodes ont été insérées dans le plexus ganglionnaire droit antérieur (PGDA) pour enregistrer les décharges neuronales.

La SHF a induit le ralentissement de la fréquence sinusale (FS) dans le plexus ganglionnaire supérieur gauche (PGSG). La LL-CBS a induit une augmentation progressive dans le S-FA et la PREO à tous les sites et une diminution significative dans le calcul de la FV à 2 heures (tous P < 0,05). La LL-CBS a inhibé la capacité de stimulation du PGSG à ralentir la FS et les valeurs moyennes de la fréquence et de l'amplitude de l'activité neuronale du PGAD comparativement au groupe de traitement fictif (tous P < 0,05).

La LL-CBS supprime l'inductibilité de la FA en inhibant l'activité neuronale des plexus ganglionnaires. La LL-CBS pourrait servir de nouvelle modalité thérapeutique pour traiter la FA.

Chemical transmission is the fundamental mode of communication in the nervous system that depends on receptors in the plasma membrane for sensing released neurotransmitter and for producing an appropriate, well-timed response. Two distinct types of receptors mediate this process: ionotropic and G-protein coupled. Ionotropic receptors are protein complexes and, through transmitter binding, conformational changes are induced that directly open a pore to permit ion flow. Ionotropic receptors produce the majority of excitatory and inhibitory signals required for rapid signaling in the central and peripheral nervous system. G-protein coupled receptors (GPCRs) are monomeric or dimeric complexes that mediate their effects by coupling to G-proteins when bound to transmitter. GPCRs typically produce slower onset and longer duration responses because their activation often leads to a series of enzymatic steps that alter the metabolism of the cell. The structure and function of these receptor molecules is the focus of this chapter.

Okadaic acid (OKA) is one of the main polyether toxins produced by marine microalgae which causes diarrhetic shellfish poisoning. It is a selective and potent inhibitor of serine/threonine phosphatases 1 and 2A induces hyperphosphorylation of tau in vitro and in vivo. The reduced activity of phosphatases like, protein phosphatase 2A (PP2A) has been implicated in the brain of Alzheimer's disease (AD) patients. It is reported that AD is a complex multifactorial neurodegenerative disorder and hyperphosphorylated tau proteins is a major pathological hallmark of AD. The molecular pathogenesis of AD includes an extracellular deposition of beta amyloid (Aβ), accumulation of intracellular neurofibrillary tangles (NFT), GSK3β activation, oxidative stress, altered neurotransmitter and inflammatory cascades. Several lines of evidence suggested that the microinfusion of OKA into the rat brain causes cognitive deficiency, NFTs-like pathological changes and oxidative stress as seen in AD pathology via tau hyperphosphorylation caused by inhibition of protein phosphatases. So, communal data and information inferred that OKA induces neurodegeneration along with tau hyperphosphorylation; GSK3β activation, oxidative stress, neuroinflammation and neurotoxicity which is a characteristic feature of AD pathology. Through this collected evidence, it is suggested that OKA induced neurotoxicity may be a novel tool to study Alzheimer's disease pathology and helpful in development of new therapeutic approach.