1、Chapter 12 Other neurotransmittersSection I: HistamineRecognition 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, endotheli

2、al cellH2-receptor antagonists as drugs curing peptic ulcerMechanism of actionCompetitively 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 v

3、agal stimulated and gastrin stimulated acid secretion. complete inhibition has not been shownH2-receptor antagonistsFour 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 羅沙替丁The L-amino-acid-transporter brings histidine into neuron

4、s 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-methylh

5、istamine, a metabolite that does not show any histamine-like activity.1. Histamine transport and metabolism in neurons2. Histaminergic neurons 1) Location and projections: localized distribution of cell body and widespread projections of monoaminergic systems. 2) Sites of synapses: dendrites (predom

6、inately), 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.Obvio

7、us afterhyperpolariztion (AHP): voltage-gated K current, calcium-dependent K current.e. H3 autoreceptors regulate the firing rate: inhibition of VDCCs.I-clampV-clamp(H3 receptor antagonist)Please describe the firing properties of histaminergic neurons and the mechanisms.Question3. Histaminergic rece

8、ptors hyperpolarizing-activated cation currentH1 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 accommodati

9、on 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

10、 of the CNS 1) Arousal4. Histamine and the function of the CNS 2) Maintenance of endohomeostasisWater balance: H1 receptor vasopressinFeeding Thermal regulationCardiovascular regulationstressVasopressin releaseHistamineA-FMH,H3 agonists, postsynaptic histmine antagonists(-)3) Learning and memory: pe

11、ople predisposed to allergy smarter? 4. Histamine and the function of the CNS 4) Emotion and anxiety 5) Pain modulationSection II: nitric oxideRobert F Furchgott, born 1916Dept. of Pharmacology,SUNY Health Science CenterNew YorkLouis J Ignarro, born 1941Dept. of Molecular and Medical PharmacologyUCL

12、A School of MedicineLos AngelesFerid Murad, born 1936Dept. of Integrative BiologyPharmacology and PhysiologyUniversity of Texas Medical School, HoustonFerid Murad, born 1936Dept. of Integrative BiologyPharmacology and PhysiologyUniversity of Texas Medical School, HoustonFerid Murad, born 1936Dept. o

13、f Integrative BiologyPharmacology and PhysiologyUniversity of Texas Medical School, HoustonFerid Murad, born 1936Dept. of Integrative BiologyPharmacology and Physiology, University of Texas Medical School, HoustonResearch on gaseous nitric oxide began when Furchgott and Zawadzki showed that the rela

14、xation 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

15、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 cardiov

16、ascular system. 1. Biosynthesis and enzymeNameGene(s)DescriptionNeuronal NOS (nNOS or NOS1)NOS1Produces NO in neuronal tissue in both the central and peripheral nervous system. Neuronal NOS also performs a role in cell communication and is associated with plasma membranes.Inducible NOS (iNOS or NOS2

17、)NOS2A, NOS2B, NOS2CCan be found in the immune system but is also found in the cardiovascular system. It uses the oxidative stress of NO (a free radical) to be used by macrophages in immune defence against pathogens.Endothelial NOS (eNOS or NOS3 or Constitutive / cNOS)mNOS NOS3Generates NO in blood

18、vessels and is involved with regulating vascular function. A constitutive Ca2+ dependent NOS provides a basal release of NO. eNOS is associated with plasma membranes surrounding cells and the membranes of Golgi bodies within cells.?When exposed to oxygen, NO is converted into NO2.2NO + O2 2NO2 This

19、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 actions3. NO and the CNSLeaning and memory: modulation o

20、f LTP.Modulation of neurotransmission4. NO and the EDSection 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 terminalsn

21、eurotransmitter?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 degra

22、dation of ATP. 2. Purinoceptors Classification P1（adenosine）receptorP2（nucleotide） receptorP2XP2YSubtypesA1，A2A，A2B，A3P2X1-7P2Y1，P2Y2，P2Y4，P2Y6，P2Y11-14Receptor typesG-protein-coupled receptorsLigand-gated ion chennelsG-protein-coupled receptorsEndogenous ligandadenosineATPATP，ADP，UTP，UDP(1) P1 rece

23、ptors?question喝咖啡提神的神經機制如何？(2) P2 receptorsP2X receptorsNucleotide-gated non-selective cation channels.Homomeric or heteromeric trimer.Each subunit has two transmembrane domains. Each receptor has three subunit.Functionally excitatory.(2) P2 receptors2) P2Y receptorsG-protein-coupled receptors.Funct

24、ionally mainly inhibitory: inhibit AC, activate PLC3. Purine and CNS functionAdenosineNon-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) ATPIn 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) ATPIn PNS:As the co-localized neurotransmitter of the autonomic