Neuropeptides

Atopic dermatitis (AD) and psoriasis (Pso) are two common inflammatory skin diseases which are symptomatically characterized by pruritus to variable degrees. Whereas AD is nearly always associated with pruritus, only 50%-70% of patients with Pso suffer from itching. Within the last decade, the development of biologic agents targeting specific cytokines or cytokine receptors has led to tremendous progress in suppressing inflammation (and thus improving quality of life) in these two diseases. While suppressing inflammation would generally reduce pruritus in these inflammatory diseases, pruritus is still recalcitrant for treatment in some patients due to relative lack of therapeutics that specifically inhibit pruritus signaling. There is abundant evidence that certain cytokines and neuropeptides-ion channels signaling mediate pruritus that is independent of inflammation in AD and psoriasis. Of note, Janus kinase (JAK) and nerve growth factor (NGF)-tropomyosin receptor kinase A (TrkA)-transient receptor potential vanilloid 1 (TRPV1) signaling partially regulates pruritus in AD and psoriasis. JAK kinases inhibitors decrease the extent of itch in patients with AD and Pso. In clinical trials, topical inhibitors of TrkA and TRPV1 have been reported to reduce pruritus in patients with Pso and AD, respectively. In this article, we review recent literature knowledge regarding the mechanisms underlying pruritus in AD and Pso, providing hypotheses for why pruritus may be more common in AD than in Pso. In light of the different mechanisms underlying these two diseases, the current and developing therapeutics, either in human clinical trials or animal studies, for targeting pruritus are also discussed.

Recent studies have implicated the orexin system as a critical regulator of sleep/wake states, feeding behavior, and reward processes. Orexin deficiency results in narcolepsy-cataplexy in humans, dogs, and rodents, suggesting that the orexin system is particularly important for maintenance of wakefulness. Orexin agonists and antagonists are thought to be promising avenues toward the treatment of sleep disorders, eating disorders, and drug addiction. In this chapter, we discuss the current understanding of the physiological roles of orexins in regulation of arousal, sleep/wake states, energy homeostasis, and reward systems.

1. The morphology of bacteria treated with the bactericidal glycoprotein, Achacin, purified from the giant African snail, Achatina fulica Férussac, has been studied. 2. Achacin lengthens the bodies of Escherichia coli by three to seven times. 3. Achacin damages the surface of Staphylococcus aureus and sinks the cytoplasmic membranes into the cytoplasm. 4. Achacin causes neither the leakage nor the destruction of cells.

Metabotropic glutamate receptors (mGluRs) can increase intracellular Ca2+ concentration via Ins(1,4,5)P3- and ryanodine-sensitive Ca2+ stores in neurons. Both types of store are coupled functionally to Ca2+-permeable channels found in the plasma membrane. The mGluR-mediated increase in intracellular Ca2+ concentration can activate Ca2+-sensitive K+ channels and Ca2+-dependent nonselective cationic channels. These mGluR-mediated effects often result from mobilization of Ca2+ from ryanodine-sensitive, rather than Ins(1,4,5)P3-sensitive, Ca2+ stores, suggesting that close functional interactions exist between mGluRs, intracellular Ca2+ stores and Ca2+-sensitive ion channels in the membrane.

Neurohormones similar to those of mammals are carried in fish by hypothalamic nerve fibers to regulate directly follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Gonadotropin-releasing hormone (GnRH) stimulates the secretion of FSH and LH and the expression of the glycoprotein hormone alpha (GPalpha), FSHbeta, and LHbeta, as well as their secretion. Its signal transduction leading to LH release is similar to that in mammals although the involvement of cyclic AMP-protein kinase A (cAMP-PKA) cannot be ruled out. Dopamine (DA) acting through DA D2 type receptors may inhibit LH release, but not that of FSH, at sites distal to activation of protein kinase C (PKC) and PKA. GnRH increases the steady-state levels of GPalpha, LHbeta, and FSHbeta mRNAs. Pituitary adenylate cyclase-activating polypeptide (PACAP) 38 and neuropeptide Y (NPY) potentiate GnRH effect on gonadotropic cells, and also act directly on the pituitary cells. Whereas PACAP increases all three subunit mRNAs, ...

Background: Impairment of sleep–wake cycles and circadian rhythm are found in human narcolepsy which is characterized by deficiency of hypocretin (hcrt) or its receptors. A disturbed electroencephalography (EEG) based vigilance regulation is also found in affective disorders such as major depressive disorder (MDD) and mania. For the first time, in the present study hcrt levels were investigated in patients with

Abstract: The peptide neurotransmitter Phe-Met-Arg-PheNH2 (FMRFamide) increases outward K+ currents and promotes dephosphorylation of many phosphoproteins in Aplysia sensory neurons. We examined FMRFamide-induced current responses in sensory neurons injected with thiophosphorylated protein phosphate inhibitor-1 and inhibitor-2 (I-1 and I-2), two structurally different vertebrate protein phosphatase-1 (PP1) inhibitors to define a role for PP1 in the physiological actions of FMRFamide. Thiophosphorylated I-1 and I-2 both reduced the amplitude of outward currents elicited by FMRFamide by 50–60% and were as effective as microcystin-LR, which inhibited both PP1 and protein phosphatase-2A in Aplysia neuronal extracts. These data suggested that of the two major neuronal protein serine/threonine phosphatases, FMRFamide utilized primarily PP1 to open serotonin-sensitive K+ (S-K+) channels. Earlier studies showed that a membrane-associated phosphatase regulated S-K+ channels in cell-free patches from sensory neurons. Utilizing its unique substrate specificity and inhibitor sensitivity, we have characterized PP1 as the principal protein phosphatase associated with neuronal plasma membranes. Two protein phosphatase activities (apparent Mr values of 170,000 and 38,000) extracted from crude membrane preparations from the Aplysia nervous system were shown to be isoforms of PP1. These biochemical and physiological studies suggest that PP1 is preferentially associated with neuronal membranes and that its activity may be required for the induction of outward K+ currents in the Aplysia sensory neurons by FMRFamide.