ap 151

1. AP 151 The Physiology of Neurotransmitters An excellent resource for this unit can be found at the following link: http://nba.uth.tmc.edu/neuroscience/index.htm

3. Synapses

4. Electrical Synapses Pre- and postsynaptic neurons joined by gap junctions allow local current to flow between adjacent cells. Connexons: protein tubes in cell membrane. Rare in CNS or PNS Found in cardiac muscle and many types of smooth muscle. Action potential of one cell causes action potential in next cell, almost as if the tissue were one cell. Important where contractile activity among a group of cells important.

5. Chemical Synapses Most common type Cells not directly coupled as in electrical synapses Components Presynaptic terminal Synaptic cleft Postsynaptic membrane (PSM) Chemical neurotransmitters (NT�s) released by presynaptic neuron NT binds to receptor on PSM

6. Chemical Synapse

7. Removal of Neurotransmitter from Synaptic Cleft

8. Synaptic Delay 0.2-0.5 msec delay between arrival of AP at synaptic knob and effect on PSM Reflects time involved in Ca++ influx and NT release While not a long time, its cumulative synaptic delay along a chain of neurons may become important. Thus, reflexes important for survival have only a few synapses Synaptic Fatigue Under intensive stimulation, resynthesis and transport of recycled NT my be unable to keep pace with demand for NT Synapse remains inactive until NT has been replenished

9. Receptor Molecules and Neurotransmitters Neurotransmitter only "fits" in one receptor. Not all cells have receptors. Neurotransmitters are commonly classified as excitatory or inhibitory. Classification is useful but not precise. For example: ACh is stimulatory at neuromuscular junctions (skeletal) ACh is inhibitory at neuromuscular junction of the heart ? Therefore, effect of NT on PSM depends on the type of receptor, and not nature of the neurotransmitter Some neurotransmitters (norepinephrine) attach to the presynaptic terminal as well as postsynaptic and then inhibit the release of more neurotransmitter.

10. NT affects the postsynaptic membrane potential Effect depends on: The amount of neurotransmitter released The amount of time the neurotransmitter is bound to receptors The two types of postsynaptic potentials are: EPSP � excitatory postsynaptic potentials IPSP � inhibitory postsynaptic potentials Postsynaptic Potentials

11. EPSPs are graded potentials that can initiate an action potential in an axon Use only chemically gated channels Postsynaptic membranes do not generate action potentials But, EPSPs bring the RMP closer to threshold and therefore closer to an action potential Excitatory Postsynaptic Potentials

12. Neurotransmitter binding to a receptor at inhibitory synapses: Causes the membrane to become more permeable to potassium and chloride ions Leaves the charge on the inner surface more negative (flow of K+ out of the cytosol makes the interior more negative relative to the exterior of the membrane Reduces the postsynaptic neuron�s ability to produce an action potential Inhibitory Synapses and IPSPs

13. A single EPSP cannot induce an action potential EPSPs must summate temporally or spatially to induce an action potential Temporal summation � one presynaptic neuron transmits impulses in rapid-fire order Spatial summation � postsynaptic neuron is stimulated by a large number of presynaptic neurons at the same time IPSPs can also summate with EPSPs, canceling each other out Summation

14. Summation

16. Chemicals used for neuronal communication with the body and the brain 50 different neurotransmitters have been identified Classified chemically and functionally Chemically: ACh, Biogenic amines, Peptides Functionally: Excitatory or inhibitory Direct/Ionotropic (open ion channels) Indirect/metabotropic (activate G-proteins) that create a metabolic change in cell Neurotransmitters

17. Direct: neurotransmitters that open ion channels Promote rapid responses Examples: ACh and amino acids Indirect: neurotransmitters that act through second messengers Promote long-lasting effects Examples: biogenic amines, peptides, and dissolved gases Neurotransmitter Receptor Mechanisms

18. Composed of integral membrane protein Mediate direct neurotransmitter action Action is immediate, brief, simple, and highly localized Ligand binds the receptor, and ions enter the cells Excitatory receptors depolarize membranes Inhibitory receptors hyperpolarize membranes Channel-Linked Receptors

19. Channel-Linked Receptors

20. Responses are indirect, slow, complex, prolonged, and often diffuse These receptors are transmembrane protein complexes Examples: muscarinic ACh receptors, neuropeptides, and those that bind biogenic amines G Protein-Linked Receptors

21. Neurotransmitter binds to G protein-linked receptor G protein is activated and GTP is hydrolyzed to GDP The activated G protein complex activates adenylate cyclase Adenylate cyclase catalyzes the formation of cAMP from ATP cAMP, a second messenger, brings about various cellular responses G Protein-Linked Receptors: Mechanism

22. G Protein-Linked Receptors: Mechanism

23. G protein-linked receptors activate intracellular second messengers including Ca2+, cGMP, and cAMP Second messengers: Open or close ion channels Activate kinase enzymes (phosphorylation rxn�s) Phosphorylate channel proteins Activate genes and induce protein synthesis!! G Protein-Linked Receptors: Effects

24. Acetylcholine (ACh) Biogenic amines Amino acids Peptides Novel messengers: ATP and dissolved gases NO and CO Chemical Neurotransmitters

25. First neurotransmitter identified (by Otto Loewi) and best understood Synthesized and enclosed in synaptic vesicles Degraded by the enzyme acetylcholinesterase (AChE) Released by cholinergic neurons: All skeletal muscle motor neurons Anterior horn motor neuron (= Lower motor neuron) Some neurons in the autonomic nervous system All ANS preganglionic neurons (parasym. and sympathetic) All parasympathetic postganglionic neurons stimulating smooth muscle, cardiac muscle, and glands Symp. postganglionic neurons stimulating sweat glands Ach binds to cholinergic receptors known as nicotinic or muscarinic receptors Neurotransmitters: Acetylcholine

26. Comparison of Somatic and Autonomic Systems

27. Cholinergic Receptors: Bind ACh Nicotinic receptors - Are ion channels (rapid acting) - On sarcolemma of skeletal muscle fibers - On dendrites and cell bodies of ALL postganglionic neurons of the ANS - Excitatory (open Na+ channels ? fast EPSP) Muscarinic receptor - Are G-protein couple receptors (complex intracellular functions) - On all parasympathetic target organs (cardiac and smooth muscle) - Are excitatory in most cases; inhibitory in others

28. Effects prolonged (leading to tetanic muscle spasms and neural �frying�) by nerve gas and organophosphate insecticides (Malathion). ACH receptors destroyed by patients own antibodies in myasthenia gravis Binding to receptors inhibited by curare (a muscle paralytic agent blowdarts in south American tribes and some snake venoms.

29. Include: Catecholamines � dopamine, norepinephrine (NE), and epinephrine (EP) Indolamines � serotonin and histamine Broadly distributed in the brain Cats. are important sympathetic NTs Play roles in emotional behaviors and our biological clock Neurotransmitters: Monoamines/Biogenic Amines

30. Synthesis of Catecholamines AA tyrosine is parent cpd Enzymes present in the cell determine length of biosynthetic pathway Norepinephrine and dopamine are synthe-sized in axonal terminals Epinephrine is released by the adrenal medulla as a hormone

31. Norepinephrine (aka Noradrenaline) Main NT of the sympathetic branch of autonomic nervous system Binds to adrenergic receptors (? or ? -many subtypes, ?1, ?2, etc) Excitatory or inhibitory depending on receptor type bound Very important role in attention and arousal - an organisms vigilance Also released by adrenal medulla as a hormone �Feeling good� NT Clinical Importance Thought to be involved in etiology of some bipolar affective disorders Removal from synapse blocked by antidepressants and cocaine Levels lowers in depressed pts. and higher in manic phase of bipolar dis. Release enhanced by amphetamines

32. BIOGENIC AMINES: Dopamine Dopamine Binds to dopaminergic receptors of substantia nigra of midbrain and hypothalamus Involved in important physiology functions including: Motor control Coordinating autonomic functions Regulating hormone release Motivational behavior and reward; i.e., a �feeling good� NT Hypothesized to be at the heart of the mechanisms of ALL addictive- drugs and behaviors. For example, Release enhanced by amphetamines Reuptake blocked by cocaine Deficient in Parkinson�s disease Receptor abnormalities have been linked to development of schizo- phrenia

33. Biogenic Amines: Serotonin (5-HT) Synthesized from the amino acid tryptophan Since tryptophan not synthesized in humans, its levels available for synthesis of serotonin are dependent on diet. Diets high in tryptophan can markedly elevate serotonin levels May play a role in sleep, appetite, and regulation of moods (aggression) Low 5-HT levels associated with increased aggressiveness and risk taking Acts in a pathway that monitors carbohydrate intake, acting as a negative regulator of motivation to ingest carbohydrate Has led to the use of SSRIs (see below) as obesity pills (fenfluramine) Drugs that block its uptake relieve anxiety and depression and aggression SSRI�s = selective serotonin reuptake inhibitors Include drugs such as Prozac, Celexa, Lexapro, Zoloft Ecstasy targets serotonin receptors

34. Include: GABA � Gamma (?)-aminobutyric acid Glycine Aspartate Glutamate Found only in the CNS Neurotransmitters: Amino Acids

35. Amino Acid Neurotransmitters Excitatory Amino Acids 1. Glutamate Indirect action via G proteins and 2nd messengers Direct action -- opens Ca++ channels (ionotropic) NMDA receptors (have a high permeability to Ca++) Widespread in brain where it represents the major excitatory neurotransmitter Important in learning and memory! Highly toxic to neurons when present for extended periods - �Stroke NT� -excessive release produces excitotoxicity: neurons literally stimulated to death; most commonly caused by ischemia due to stroke (Ouch!) Aids tumor advance when released by gliomas (ouch!)

36. Amino Acids

37. Neuropeptide receptors are all G-protein linked Alter levels of intracellular second messengers Include: Substance P � mediator of pain signals Neuropeptide Y - stimulates appetite and food intake Beta endorphin, dynorphin, and enkephalins Opiods: include Endorphins, Enkephalins, Dynorphin Act as natural opiates, reducing our perception of pain Found in higher concentrations in marathoners and women who have just delivered Bind to the same receptors as opiates and morphine Neurotransmitters: Peptides

38. Nitric oxide (NO) Same substance produced by sublingual nitroglycerin produces to increase vasodilation in relief of angina A short-lived toxic gas; diffuses through post-synaptic membrane to bind with intracellular receptor (guanynyl cyclase) Is a free radical and therefore highly reactive compound Do not confuse with �laughing gas� (nitrous oxide) Is involved in learning and memory Important in control of blood flow through cerebro-vasculature Some types of male impotence treated by stimulating NO release (Viagra) Viagra ? NO release ? smooth muscle relaxation ? increased blood flow ? erection Can�t be taken when other pills to dilate coronary b.v. taken Neurotransmitters: Novel Messengers

39. Two classifications: excitatory and inhibitory Excitatory neurotransmitters cause depolarizations (e.g., glutamate) Inhibitory neurotransmitters cause hyperpolarizations (e.g., GABA) Functional Classification of Neurotransmitters

40. Some neurotransmitters have both excitatory and inhibitory effects Determined by the receptor type of the postsynaptic neuron Example: acetylcholine Excitatory at neuromuscular junctions with skeletal muscle (nicotinic receptor) Inhibitory in cardiac muscle (muscarinic receptor) Functional Classification of Neurotransmitters