2013神经递质组胺等wjj课件

Chapter 12 Other neurotransmitters,Wang Jijiang,Section I: Histamine,Recognition of histamine as an intercellular messenger: Anaphylaxis (allergy) Arousal,Distribution Peripheral: mastocyte, basicyte. Central: Neuronal histamine in tuberomammillary nucleus (TMN). Non-neuronal histamine: mastocyte, glia cell, endothelial cell,H2-receptor antagonists as drugs curing peptic ulcer,Mechanism of action Competitively block the histamine (H2) receptor of acid-producing parietal cells rendering cells less responsive to not only histamine but also to the stimulation of acetylcholine and gastrin. Also up to 90% inhibition of vagal stimulated and gastrin stimulated acid secretion. complete inhibition has not been shown,H2-receptor antagonists,Four FDA-approved: Cimetidine 西咪替丁 （Tagamet） Ranitidine 雷尼替丁 （Zantac） Famotidine 法莫替丁（Pepcid） Nizatidine 尼扎替丁 （Axid） Roxatidine 罗沙替丁,The L-amino-acid-transporter brings histidine into neurons where histamine is synthesized by the specific enzyme histidine decarboxylase. Histamine is then taken up into vesicles by the vesicular monoamine-transporter VMAT-2. After release, histamine is methylated by histamine methyltransferase which is located postsynaptically and in glia to tele-methylhistamine, a metabolite that does not show any histamine-like activity.,1. Histamine transport and metabolism in neurons,2. Histaminergic neurons,1) Location and projections: localized distribution of cell body and widespread projections of monoaminergic systems. 2) Sites of synapses: dendrites (predominately), cell body (less). 3) Co-localization with other neurotransmitters and neuro-modulators,2. Histaminergic neurons,4) Firing properties: Spontaneously active: pace-maker property. Mechanism: persistent sodium current; voltage-gated calcium current. b. Low firing frequency: Longer AP duration. Obvious afterhyperpolariztion (AHP): voltage-gated K current, calcium-dependent K current. e. H3 autoreceptors regulate the firing rate: inhibition of VDCCs.,I-clamp,V-clamp,(H3 receptor antagonist),Please describe the firing properties of histaminergic neurons and the mechanisms.,Question,3. Histaminergic receptors,hyperpolarizing-activated cation current,H1 receptors. Depolarization of a neuron of the pontine reticular formation through block of a K+ conductance.,H2 receptors. Block of the long-lasting afterhyperpolarization after Ca2+-inflow (calcium-dependent K+ conductance) and block of the accommodation of action potential firing in a human hippocampal pyramidal cell.,H3 receptors. Decrease of field excitatory postsynaptic potential in the dentate gyrus of the hippocampus evoked by perforant path stimulation. Histamine reduced the release of glutamate in this pathway.,4. Histamine and the function of the CNS,1) Arousal,4. Histamine and the function of the CNS,2) Maintenance of endohomeostasis Water balance: H1 receptor vasopressin Feeding Thermal regulation Cardiovascular regulation,stress,Vasopressin release,Histamine,A-FMH,H3 agonists, postsynaptic histmine antagonists (-),3) Learning and memory: people predisposed to allergy smarter?,4. Histamine and the function of the CNS,4) Emotion and anxiety,5) Pain modulation,Section II: nitric oxide,Robert F Furchgott, born 1916 Dept. of Pharmacology, SUNY Health Science Center New York,Louis J Ignarro, born 1941 Dept. of Molecular and Medical Pharmacology UCLA School of Medicine Los Angeles,Ferid Murad, born 1936 Dept. of Integrative Biology Pharmacology and Physiology, University of Texas Medical School, Houston,Research on gaseous nitric oxide began when Furchgott and Zawadzki showed that the relaxation of blood vessels depended on an intact endothelium. Murad et al showed that nitroglycerine caused blood vessels to relax, and that this was caused by the release of nitric oxide gas. Ignarro et al demonstrated that the relaxation of blood vessels described by Furchgott was due to a substance produced in the endothelium, which his group called endothelium-derived relaxing factor (EDRF). In 1987, Ignarro demonstrated that EDRF was, indeed, nitric oxide. In 1998, these three individuals won the Nobel Prize for their discoveries concerning nitric oxide as a signaling molecule in the cardiovascular system.,1. Biosynthesis and enzyme,When exposed to oxygen, NO is converted into NO2. 2NO + O2 2NO2 This conversion has been speculated as occurring via the ONOONO intermediate. In water, NO react with oxygen and water to form HNO2 or nitrous acid. The reaction is thought to proceed via the following stoichiometry: 4 NO + O2 + 2 H2O 4 HNO2,2. Cell actions,3. NO and the CNS,Leaning and memory: modulation of LTP. Modulation of neurotransmission,4. NO and the ED,Section II: purine and pyridine,History of purine and pyridine as neurotransmitter: Drury et al 1929: vasodilatation. Gillespie 1934: differential effects of adenosine and ATP on blood vessels. Holton 1953: release of ATP at sensory neural terminalsneurotransmitter? Burnstock 1972: concept of purinergic nerve (future Nobel prize?).,Recourses of extracellular adenosine and ATP,Extracellular ATP: from vesicle excytosis; from broken cells. Intracellular adenosine, AMP, and ADP: transported from the inside of cells by nucleotide transporter. from degradation of ATP.,2. Purinoceptors,(1) P1 receptors,?,question,喝咖啡提神的神经机制如何？,(2) P2 receptors,P2X receptors Nucleotide-gated non-selective cation channels. Homomeric or heteromeric trimer. Each subunit has two transmembrane domains. Each receptor has three subunit. Functionally excitatory.,(2) P2 receptors,2) P2Y receptors G-protein-coupled receptors. Functionally mainly inhibitory: inhibit AC, activate PLC,3. Purine and CNS function,Adenosine Non-traditional release: not released in quanta. Presynaptic and postsynaptic inhibition. Important in sleep and wakefulness, emotion and anxiety, and learning and memory.,3. Purine and CNS function,(2) ATP,In CNS: Presynaptic action: modulate release of other neurotransmitters. Postsynaptic action: modulate the responses of other neurotransmitters. Actions on glia cells and intermediate neurons.,3. Purine and CNS function,(2) ATP,In PNS: As the co-localized neurotransmitter of the autonomic nerves. Sensitization of the noceceptive nerves. Modulation of the chemical reflex.,As the co-localized neurotransmitter of the auton