Nervous System Introduction PDF

Used sources; Recommended readings  Textbook of Medical Physiology – Arthur C. Guyton ve John E. Hall  Review of Medical Physiology : – Kim E. Barrett, Susan M. Barman, Scott Boitano, Heddwen L. Brooks  Medical Physiology - Principles for Clinical Medicine  Yazar: Rodney A. R...

Used sources; Recommended readings  Textbook of Medical Physiology – Arthur C. Guyton ve John E. Hall  Review of Medical Physiology : – Kim E. Barrett, Susan M. Barman, Scott Boitano, Heddwen L. Brooks  Medical Physiology - Principles for Clinical Medicine  Yazar: Rodney A. Rhoades ve David R. Bell  İnsan Fizyolojisi  Fizyoloji Derneği  Internet  Introduction to Central Nervous System Central nervous system-Introduction  Next / Today’s topic’s learning objectives  At the end of this lecture you will be able: – To relate function of brain and neuron – To decribe parts of neuons, – To list ion channels involved in generation of action potential – To decribe types of propagation of action potential – To describe types of postsynaptic potentials – To explain neuromuscular junction and transmission Prof.Dr. Ramazan Bal  What does nervous system do?  Nervous system – Pick up signals from internal and external environment – Conduct these signals to the CNS – Integrate these signals in order to form immediate or delayed responses such as, – thoughts, – senses, – movements, – balance, and so on  Functions of the nervous system  Functions of the nervous system: – Sensory system – Motor system – Limbic system –behaviour - motivation – Sleep-wakefulnes – Thinking –thoughts – Planning – Learning and memory – Intellegence – Consciousness  Neurons  There are 100 trillion cells in the body – Of which, 100 billion are in the brain  What is the main defining characteristic of neurons? – have the property of electrical excitability - ability to produce action potentials or impulses in response to stimuli  Neurons Cell body (soma)  Soma: Cell body; metabolic center of neuron; – İntegrates signals  Nucleus (contains genetic material) with prominent nucleolus (high synthetic activity)  Nissl bodies: rough ER & free ribosomes for protein synthesis – proteins were used to replace neuronal cellular components for growth and repair of damaged axons in the PNS  Neurofilaments (neurofibrils): bundles of intermediate filaments & give cell shape &support  Microtubules move material inside the cell  Neurons Dendrites (little trees)  Dendrites receive messages from other neurons;  Short, tapering and highly branched  Input portion of the neuron  Neurons Axon & Dendrites Axon Carries information away from the cell body; longest part of neuron  Conduct impulses away from cell body  impulses arise at the junction of axon hillock &initial segment of axon  Swollen tips called synaptic end bulbs contain vesicles filled with neurotransmitters  Axon end in fine processes called axon terminals – cytoplasm = axoplasm – plasma membrane = axolemma – Axon collaterals arise from the axon  Axonal Transport  Cell body is location for most protein synthesis (FE: neurotransmitters & repair proteins) – However the axon or axon terminals require proteins e.g. neurotransmitters (1). Slow axonal flow  Axoplasm move in only anterograde direction away from cell body at 1-5 mm/day  Replenishes axoplasm in regenerating or maturing neurons retrograde anterograde  Axonal Transport (2). Fast axonal flow Axonal microtubules are used as tracks  moves organelles & materials along surface of microtubules at 200-400 mm per day  Transports material in either direction for use in terminals or for recycling in cell body – Degenerating mitochondria is transported in the retrograde direction for recycing – New mitochondria move down axon in anterograde direction  Axonal Transport (2). Fast axonal flow  Polypeptides packaged into vesicules are attached to the motor molecules, – Movement in the anterograde direction is mediated by the molecular motor kinesin – But the force necessary to move organelles retrograde direction is generated by dynein  Types of glial cells A. Microglia – Act as phagocytes; clear away dead cells – Protect CNS from disease through phagocytosis of microbes – Migrate to areas of injury where they clear away debris of injured cells Prof.Dr. Ramazan Bal  Types of glial cells B. Macroglia  1. Astrocytes: Star shaped with many processes – Form blood-brain barrier: processes wrap around blood capillaries, – Regulate nutrient concentrations for neuron survival – Maintain appropriate pH & [K+] for action potential generation by neurons – Take up excess neurotransmitters – Assist in neuronal migration during brain development – Perform repairs to stabilize tissue – scar formation (?) Prof.Dr. Ramazan Bal  Types of glial cells B. Macroglia  2. Oligodendroglia: myelinate axons of central nervous system (CNS)  4. Schwann cells: myelinate axons of peripheral nervous system(PNS)  5. Ependymal Cells – Form epithelial membrane lining cerebral cavities that contain CSF – Produce & circulate CSF found in these chambers  6. Satellite Cells – Flat cells surrounding peripheral axonsSupport neurons in the PNS Prof.Dr. Ramazan Bal Prof.Dr. Ramazan Bal  Nerve action potential  Nerve signals are transmitted by action potentials  Action potential is rapid changes in resting membrane potential that spread rapidly along the nerve fiber membrane – a sudden change from the normal resting membrane potential to a (+)potential and then back to normal resting membrane potential  At rest, before action potential begins, conductance for K+ is ~75times more than that for Na+  The membrane is polarized   Nerve action potential  At the onset of action potentials, Na channels become activated – Na conductance increases by 5000-fold leading to Na influx. – membrane potential shift rapidly in positive direction (Depolarization)  Within milliseconds, Na channels begin to close &K channels open more – The onset of the action potential also causes openning of K+channels more slowly – Then, rapid diffusion of K+ efflux establishes the normal negative resting membrane potential (repolarization) Prof.Dr. Ramazan Bal Na Kanalı K Kanalı Aktivasyon kapısı At rest At rest Hyperpolarization After hyperpolarizing potential (AHP) Na+-K+ pump are operate continiously whenever Na+and K+ gradienst are disturbed by leak channels &gated channels Leak channels are open all the time: It is more permiable to K ion than Na by 75-100 times  Receptor potantiel - Graded potentials  When ion channels open with stimuli in receptors – receptor potantiel is generated  Receptor potentials are not action potential and therefore they are not all-or-none – If the receptor potential rises above the threshold – Action potential occur in the nerve fiber attached to the receptor, Prof.Dr. Ramazan Bal  Receptor potantiel - Graded potentials  As intensity of stimuli increases – Amplitude of receptor potential increases  if amplitude of receptor potential increase – Frequency of action potential increase  Examples of graded potansiyele: – Synaptic potentials (EPSP & IPSP) – Receptor potantials Prof.Dr. Ramazan Bal Properties of Graded potentials vs Action potential 1). Graded potentials can be a depolarization or a hyperpolarization – Action potential is only a depolarization 2). Graded potentials is initiated by environment stimulus (receptor), by neurotransmitter (synapse), or spontaneously – Action potential is initiated by a graded potential Properties of Graded potentials vs Action potential 3). In graded potentials, mechanism depends on ligand-gated channels or other chemical or physical changes – In action potential mechanism depends on voltage-gated channels 4). In graded potentials amplitude varies with size of the initiating event – In action potentials, amplitude of action potential is independent of the size of the initiating event – they are all-or-none Properties of Graded potentials vs Action potential 5). Graded potentials can be summed over time (temporal summation) &across space (spatial summation) – Action potentials cannot be summed – Summation is not possible with action potentials (due to the all-or-none nature, and the presence of refractory periods) Properties of Graded potentials vs Action potential 6). Graded potentials has no threshold – Action potentials has a threshold that is usually 15 mV depolarized relative to the resting potential 7). Graded potentials has no refractory period – Action potentials has a refractory period Properties of Graded potentials vs Action potential 8). In graded potentials amplitude decreases with distance – Action potentials is conducted without decrement; – The depolarization is amplified to a constant value at each point along membrane 9) Graded potentials are not all-or-none – Action potentials are all-or-none Synapses  Learning objectives  At the end of this lecture you will be able: – To decribe anatomical structure of a synaps – To explain types of synaptic potentials – To describe types of summation of synaptic potentials Prof.Dr. Ramazan Bal  CNS Synapses (1) Electrical synapse Electrical synapses is mediated by gap junctions Gap junctions are formed from hexameric pores, called connexons (Cx36), – Connexons is an assembly of six proteins called connexins that form the pore for a gap junction – The pore is wide enough to allow ions and even medium-size molecules – In adult human no electrical synaps between neurons Prof.Dr. Ramazan Bal  CNS Synapses (1) Electrical synapse Gap junctions conduct ions freely (electricity) from one cell to the next – Gap junctions form channels between adjacent cells. Synchronize the electrical activity of large populations of neurons; Synchronization may be required for – neuronal development – synthesis and release of hormones by some neurosecretory neurons Prof.Dr. Ramazan Bal  CNS Synapses (2) Chemical synapse Almost all the synapses in the mamalian CNS is this type – Neurotransmitter is responsible for signal transmission at chemical synapse  The part of the synapse that belongs to the initiating neuron is called presynaptic membrane.  The part of the synapse that belongs to the receiving neuron is called postsynaptic membrane.  The space between the two is called the synaptic cleft (space) Prof.Dr. Ramazan Bal  Anatomy of the synapse  Human brain contain, ~1012 nöron (1.000.000.000.000= 1 trilyon); – There are 1015 synapse in the brainEach neuron has 1000 synapse in avarage – Synaptic cleft: 200-330 Angstrom  Axon Terminals make synapse with the dendrites and soma of other neurons – ~90% on the dendrites – 10% on the soma.  Prof.Dr. Ramazan Bal  Anatomy of the synapse  There are three types of synapse: – Axo-dendritic: commonest type of synapse – Axo-somatic – Axo-axonic: least frequent  Prof.Dr. Ramazan Bal  Presynaptic terminals  Synaptic Gap: Space between end of axon & postsynaptic membrane  Synaptic cleft have a width of 200-300 Ao.  The terminal has two internal structures – Transmitter vesicles contain the transmitter substance – Mitochondria provide ATP, which is used for synethesizing transmitter Prof.Dr. Ramazan Bal  Receptors for neurotransmitter  Receptors for neurotransmitter are located on the postsynaptic membrane  But presynaptic neurons may also have receptors for the transmitter that they release – They are called autoreceptors and detect the transmitter released by that neuron – The autoreceptors are metabotropic – These autoreceptors are often important for regulating the subsequent amount of transmitter release. – Best known example is serotonin autoreceptors Prof.Dr. Ramazan Bal Transmitter release from the presynaptic terminals  If an action potential depolarizes ++ the presynaptic membrane, voltage- ++ gated Ca channels open and Ca flow into the axon terminal and [Ca ]i rise Calcium in the axon terminal has two major effects: (1) Ca ions binds to calmoduline  Ca-calmodulin complex activate Ca-calmodulin dependent protein kinase (CaMK) – CaMK, in turn, phosphorilates synapsin I – Phosphorilated synapsin I uncages the vesiclesthe vesicles becomes free Normally synapsin I cages around synaptic vesicles Prof.Dr. Ramazan Bal  Transmitter release from the presynaptic terminals (2). Ca++ bind to synaptotagmin found within the membranes of the synaptic vesicles Synaptotagmin act as a Ca++ sensor – Binding of Ca++ to synaptotagmin promotes fusion of the vesicle to the presynaptic plasma membrane, since SNARE proteins (synaptobrevin, Syntaxin 1 & SNAP-25) pulls the vesicle closer to the presynaptic plasma membrane – Transmitter substance is released from the active zone in the terminal membrane into the synaptic cleft Prof.Dr. Ramazan Bal  The sequence of events that lead to postsynaptic changes – The action potential signal arrives at the axon terminal – The local depolarization causes voltage gated Ca2+ channels to open. – Ca2+ enters the presynaptic cell – Ca2+ causes vesicles filled with neurotransmitter to migrate towards the presynaptic membrane &the vesicle merges with the presynaptic membrane – Neurotransmitter is released into the synaptic cleft by exocytosis. – Transmitter diffuses through synaptic cleft & binds with receptor in postsynaptic membran – Synaptic potantial (EPSP or IPSPs) develop Prof.Dr. Ramazan Bal  Transmitter substance  Receptor molecules on postsynaptic membrane have: (1) binding component: protrudes outward from membrane (2) ionophore component: passes all the way through membrane to interior – Ionophore can be (1) an ion channel (ionotropic receptors) or – Ion channels cause transient postsynaptic neuronal changes – Ionophore can be (2) a second messenger activator (metabotropic receptors): – Second messenger causes prolonged postsynaptic excitation/inhibition Prof.Dr. Ramazan Bal  Excitatory or inhibitory receptors  Some receptors cause excitation of postsynaptic neuron (EPSP); – Opening of Na channelsNa influxdepolarisation (excitation)  Others cause inhibition of postsynaptic neuron (IPSP) – Opening of Cl- channelsCl influxrepolarisation (inhibition) Membrane potantial (mV) Repolarization Resting potantia Depolarization Hyperpolarization Time (msec) Prof.Dr. Ramazan Bal Prof.Dr. Ramazan  Excitatory postsynaptic potential (EPSP)  Discharge of axon terminals causes release of excitatory neurotransmitter, which acts on excitatory receptor – Na+ move to the interior through receptor channels depolarized to -45 mV – If reach thresholdelicit an action potentials in the initial segment of axon (axon hillox) Prof.Dr. Ramazan Bal  Excitatory postsynaptic potential (EPSP)  Axon hilox has seven times voltage-gated Na channels as does soma – EPSP of more than 15mV will elicit an action potentials  Once the action potentials begins, it travels along the axon and also backward over the soma – It may travels backward into the dendrites, but no action potentials is generated, since there is few Na channels in dendrites Prof.Dr. Ramazan Bal  Inhibitory postsynaptic potential (IPSP)  Discharge of axon terminals causes release of inhibitor neurotransmitter – inhibitor transmitter acts on inhibitory receptor  (1) Chloride ion (Cl-) move to the interior through receptor channels – Shift to more hyperpolarizing potential (-70 mV) than the rest (-65 mV) – Nernst potential for Cl-: ~-70 mV; – Major contribution Prof.Dr. Ramazan Bal  Inhibitory postsynaptic potential (IPSP)  (2) K+ efflux also make membrane potential more negative – Nernst potential for K+: ~-70-95 mV; – This inhibits the neuron – Less contribution Prof.Dr. Ramazan Bal  Summation in neurons Time course of postsynaptic potentials  EPSP due to fast neurotransmitters dies away in ~15ms.  Neuropeptide transmitters can excite /inhibit postsynaptic neuron for msec / sec / min / hours Neuropeptide: CGRP  Summation in neurons: Spatial Summation  A single terminal to cause an EPSP no greater than 0.5-1 mV: – 10-20 mV required to reach threshold for action potential.  Summing simultaneous postsynaptic potentials by activating multiple terminals  Summation in neurons: Temporal Summation  Increasing strength is by increasing frequency of nerve impulses in each fiber  Transmitter opens the membrane channels for at most a millisecons. – But the postsynaptic potential lasts up to 15 ms  So, a second opening of the same channels can increase the postsynaptic potential to a still greater level,  Successive discharges from a single presynaptic terminal, if they occur rapidly enough, can add to one another Prof.Dr. Ramazan Bal  Summation in neurons: Temporal Summation Sum of 1th & 2nd synaptic potantial Membrane potantial (mV) 1th. synaptic potantial 2nd. synaptic potantial Resting potential Time (msec) First Second stimulus stimulus  Neuromuscular junction  Synapse between a motor neuron and a skeletal muscle fiber is called neuromuscular junction  The skeletal muscle fibers are innervated by large, myelinated nerve fibers – Each nerve fiber branches and stimulates 3-500 skeletal muscle fibers – Each nerve ending makes a neuromuscular junction with the muscle fiber Prof.Dr. Ramazan Bal  Neuromuscular junction: motor end plate  Nerve terminals invaginate into the surface of the muscle fiber  The post-synaptic region at the neuromuscular junction is called the motor end plate  Space between terminal &fiber membrane is called synaptic space (cleft) – Folds of muscle membrane (subneural clefts) increase surface area at which synaptic transmitter can act – Acethylecholine receptors mainly found in subneural clefts  Acethylcholine is synthesized in the terminal, but it is absorbed into synaptic vesicles  In synaptic space, cholinesterase (acethylcholinesterase) destroys acethylcholine Prof.Dr. Ramazan Bal  Secretion of acethylcholine by the nerve terminals  As an action potential spreads, voltage-gated Ca channels open – Ca++ goes into nerve terminal  Vesicles fuse with neural membrane & empty acethylcholine into synaptic space by exocytosis Prof.Dr. Ramazan Bal  Acethylcholine on postsynaptic muscle fiber membrane  Acetylcholine binds to nicotinic acethylcholine receptor on the postsynaptic membrane – Nicotinic receptors in the muscle fiber membrane are acetylcholine-gated ion channels  Acethylcholine channel are permiable to Na+  Na+ influx creates a local positive potential change (end plate potential) – If end plate potential is above threshold, self-regenerative action potential develops – Action potential that spreads along muscle membranemuscle contraction occur Normal end plate potantial- induced action potential Curare Botilismus toxin Prof.Dr. Ramazan Bal  Destruction of released acethylcholine  Acethylcholine continues to activate acethylcholine receptors as long as acethylcholine persists in synaptic space It is removed rapidly a few milliseconds by two means: (1) Most of the acethylcholine is destroyed by acetylcholinesterase, (2) A small amount of acethylcholine diffuses out of the synaptic space  Botulinum toxin decreases the quantity of acethylcholine release by the nerve terminals. Prof.Dr. Ramazan Bal Neurotransmitters (transmitters ) & Receptors Prof.Dr. Ramazan Bal  Learning objectives  At the end of this lecture you will be able: – To list excitatory and inhibitory neurotransmitters – To explain their receptors Prof.Dr. Ramazan Bal Transmitters substances Catecholamine: hormones produced by adrenal medulla: Dopamine, Norepinephrine, Epinephrine  Glutamate  Glutamate (Excitatory Amino-Acid, EAA) is responsible for ~75 % of excitatory synapses in the CNS  Glutamate from the extracellular fluid is taken up into both glial cells &nerve terminals by glutamate transporters  Glutamate transporters contains two subclasses: – Excitatory amino acid transporters (EAATs) – Vesicular glutamate transporters (VGLUTs). Prof.Dr. Ramazan Bal  Glutamate A. Ionotropic receptors (form ligand-gated ion channels) 1). NMDA receptors increase permiability to Ca2+, Na+ &K+induce EPSP; – Important in synaptic plasticity &memory by development of LTP – At rest, NMDA receptors are blocked by Mg++ (voltage-dependent block). Mg++ block is relieved by strong depolarization, which expels Mg2+ from the pore of the NMDA receptor channel – Glycine is a required co-agonist along with glutamate for NMDA receptors – In ischemia, too much Ca influx through NMDAglutamate toxicity – Ketamine is NMDA receptor antagonists Prof.Dr. Ramazan Bal  Glutamate 2). AMPA: increases permiability to Na+ &K+’induce EPSP – AMPA reseptor subunits: GluR1, GluR2, GluR3, GluR4 3). Kainate: increases permiability to Na+ &K+’induce EPSP B. Metabotropic receptors activating ion channels through G-protein: – Metabolize IP3 increases [Ca2+]i Prof.Dr. Ramazan Bal  Acetylcholine  Acethylcholine is synthesized in the nerve terminal &then it is transported into vesicles: – Acetyl coenzyme A + choline choline acetyltransferaseacethyl choline  If acethylcholine is released into synaptic cleft acethylcholine is rapidly split again to acetate & choline – acethylcholine  cholinesterase (acethylcholinesterase )  acetate + choline  Cholinesterase (acetylcholinesterase) is attached to spongy layer of connective tissue that fills space of synaptic cleft  A small amount of acethylcholine diffuses out of the synaptic space  Prof.Dr. Ramazan Bal  Acetylcholine  Acetylcholine is secreted by the terminals of many neurons : – motor neurons that innervate the skeletal muscles – preganglionic neurons of autonomic nervous system – postganglionic neurons of parasympathetic nervous system  Acetylcholine has mostly an excitatory effect; – but it have inhibitory effects at parasympathetic nerve endings Prof.Dr. Ramazan Bal  Acetylcholine Acetylcholine activate two types of receptor: 1). Nicotinic receptors (nAChR) (ionotropic):  Responsive to nicotine: a Na+ & K+ ion channel – When acethylcholine is bound to receptor, Na+ enter the cell  Where they are found? Examples – Motor neurons that innervate the skeletal muscles – Preganglionic nerve terminal of autonomic nervous system – (The first synapse in the chain of autonomic control) Prof.Dr. Ramazan Bal  Acetylcholine 2). Muscarinic (mAChR) (metabotropic): responsive to muscarine.  Activated through G-protein  Ion channels are distant from their receptors  Where there are found? Examples – Some neurons in the basal ganglia, & cerebral cortex – Postganglionic nerve terminal of parasympathetic nervous system – (the final synapse for secondary neurons of the parasympathetic nervous system) Prof.Dr. Ramazan Bal  Acetylcholine 2). Muscarinic (mAChR) (metabotropic):  Muscarinic receptors are either excitatory or inhibitory – M1, M3, M5 receptors: activate phospholipase C, – which increases IP3 &DAG – leading to increase of intracellular [Ca++]i level – M2, M4 receptors : inhibit adenylate cyclase, which decreases level of cAMP Prof.Dr. Ramazan Bal  Norepinephrine  Catecholamines includes adrenaline, noradrenaline and dopamine  Synthesis of norepinephrine begins in the axoplasm of the terminal nerve endings of adrenergic nerve fibers but is completed inside the secretory vesicles: – The enzyme tyrosine hydroxylase in the first step is rate-limiting enzyme in the synthesis of adrenaline, noradrenaline and dopamine Prof.Dr. Ramazan Bal  Norepinephrine  After secretion of NE by the terminal nerve endings, it is removed in three ways: – (1) re-uptake into nerve endings by an active transport: ~65% of the secreted NE – (2) diffusion away into the surrounding body fluidsinto blood: most remaining NE; – (3) destruction by tissue enzymes – Monoamine oxidase (MAO) found in the nerve endings, – Catechol-O-methyl transferase (COMPT), found in diffusely in all tissues Prof.Dr. Ramazan Bal  Norepinephrine  Where there are found? Examples – Locus cerelous in pons neurons control brain activity level &wakefulness – Postganglionic neurons of sympathetic nervous system  Prof.Dr. Ramazan Bal  Norepinephrine Norepinephrine receptors:  -adrenergic receptors (1, 2)  - adrenergic receptors (1, 2) Norepinephrine & epinephrine open ion channels through second messangers:  1 affects by activation of phospholipase C (PLC), resulting in increasing [Ca++]i  2 inactivate adenylate cyclase decrease cAMP  1 &2 reseptors activate adenylate cyclase –increase cAMP –activate protein kinase –phosphorilate proteins –open ion channels Prof.Dr. Ramazan Bal  Serotonin (5-HT)  Serotonin is secreted by nuclei that originate in the median raphe of the brain stem project to many brain &spinal cord areas, especially to the dorsal horns of spinal cord and to the hypothalamus.  Functions: involved in: – Controling the mood & anxiety & aggression – Inhibiting pain pathways in the cord, – Sexual behavior, – Feeding, – Sleep wake cycle – Memory – Response to stressors – Cognition – Locomotion – Reward and decision making  Serotonin (5-HT)  There are 7 family of 5HT receptor, including 5-HT1, 2,3,4,5,6 and 7  5-HT3 receptors are ionotropic, the rest are metabotropic (G protein coupled receptor)  Serotonine released into the synaptic space is cleared by two mechanisms:  1) 5-HT is metabolised by monoamine oxidase A (MAO-A)  2) Serotonin transporter (SERT) reuptake the released serotonin – Selective serotonin reuptake inhibitor (SSRI) are used to treat mental disorders  3) Vesicular monoamine transporter (VMAT2 ) carry 5-HT into the vesicles – VMAT2 is target for psychoactive drug (amphetamine, tetrabenazine)  Dopamine  Dopamine is secreted by neurons that originate in the substantia nigra. – The effect of dopamine is usually inhibition.  Lack of dopamin in these neurons causes Parkinson disease Prof.Dr. Ramazan Bal  Dopamine Receptors  D1 & D5 receptors are couple to Gs alphastimulate adenylyl cyclase activity – D2, D3 and D4 receptors couple to Gi alphainhibit the formation of cAMP  Ultimate effect of D1-like activation (D1 and D5) can be – excitation (via opening of Na channels) or – inhibition (via opening of K channels);  Ultimate effect of D2-like activation (D2, D3, and D4) is mostly inhibition of the target neuron Prof.Dr. Ramazan Bal  Histamin  Histamine axons originate from a single source, the tuberomamillary nucleus (TMN) of the posterior hypothalamus, – They innervate almost all of the CNS regions  Active solely during waking, they maintain wakefulness and attention.  The histamine receptors are a class of G protein–coupled receptors: – H1, H2, H3, H4 receptors Prof.Dr. Ramazan Bal  Glycine  Secreted mainly at synapses in the spinal cord.  act as an inhibitory transmitter – Glycine is the smallest (20 amino acids) – Blocked by strychnine  Glycine is a required co-agonist along with glutamate for NMDA receptors in brain  Tetanus toxin blocks the release of glycine &GABA Prof.Dr. Ramazan Bal  Gamma-Aminobutryic Acid (GABA)  Secreted by nerve terminals in spinal cord, cerebellum, basal ganglia &cortex – It always cause inhibition  Synthesized from glutamate using – L-glutamic acid decarboxylase (GAD) enzyme &  Pyridoxal phosphate (which is the active form of vitamin B6) as a cofactor  B6 insufficiency result in deficiency of GABA in the brain, – which lead to neural excitability and convulsions  GABA is made primarily by the interneurons of the brain Prof.Dr. Ramazan Bal  Gamma-Aminobutryic Acid (GABA)  There are two types of GABA receptors: GABAA is an ionotropic receptor (ligand gated) selectively conducts Cl− – Responsible for most of the physiological activities of GABA in CNS GABAB is metabotropic receptors that are linked via G-proteins to K+ channels Prof.Dr. Prof.Dr.Ramazan RamazanBal Bal  Review USMLE questions  The NMDA receptor is activated by – a. Glycine – b. Acetylcholine – c. Substance P – d. Histamine – e. Glutamate  The answer is e. (Rhoades, pp 45–51.) The NMDA receptor channel is a large channel permeable to Ca2+, K+, and Na+. It is activated by glutamate, but unlike other glutamate receptor channels, the NMDA channel is blocked by Mg2+ in its resting state. Depolarization of the cell membrane to approximately −40 mV removes the Mg2+ blockade. Therefore, the NMDA channel is only opened when the cell is depolarized by other excitatory neurotransmitters. The Ca2 entering the cell activates a number of intracellular enzymes, some of which may be involved in memory.  Review USMLE questions  30. Degeneration of dopaminergic neurons has been implicated in – (A) schizophrenia – (B) Parkinson’s disease – (C) myasthenia gravis – (D) curare poisoning  The answer is B [V C 4 b (3)]. Dopaminergic neurons and D2 receptors are deficient in people with Parkinson’s disease. Schizophrenia involves increased levels of D2 receptors. Myasthenia gravis and curare poisoning involve the neuromuscular junction, which uses acetylcholine (ACh) as a neurotransmitter.  TUS-12--sinaps 16. Aşağıdakilerden hangisi adrenerjik sinaps iletiminde rol oynamaz? 2006 NİSAN A) Noradrenalin B) Mono-amino-oksidaz C) Adrenerjik reseptör D) Katekol-O-Metil-Transferaz E) Muskarinik reseptör Translation  Which of the following does not play role in adrenergic synapse transmission? – A) Noradrenalin – B) Mono-amino-oxidase E) Muskarinik reseptör – C) Adrenergic receptor – D) catechol-O-Metil-Transferase – E) Muskarinik receptor  Nervous System neurotransmitter-second messanger  Question: Which of the following autonomic drugs acts by stimulating adenylate cyclase?  (A) Atropine (reversibly inhibiting the mAChR  (B) Clonidine  (C) Curare (reversibly inhibiting the nAChR  (D) Norepinephrine  (E) Phentolamine  (F) Phenylephrine  (G) Propranolol  (D) Norepinephrine   Review USMLE questions  27. Which of the following is an inhibitory neurotransmitter in the central nervous system (CNS)? – (A) Norepinephrine – (B) Glutamate – (C) γ -Aminobutyric acid (GABA) – (D) Serotonin – (E) Histamine  The answer is C [V C 2 a–b]. γ-Aminobutyric acid (GABA) is an inhibitory neurotransmitter. Norepinephrine, glutamate, serotonin, and histamine are excitatory neurotransmitters.  Nervous System -1  Question: NMDA-receptor-dependent LTP, which is the mechanism for learning and memory, is induced if which of the following occurs?  A. Ca2+ influx during low-frequency synaptic input activates protein phosphatases.  B. γ-Aminobutyric acid (GABA) is released near an NMDA receptor.  C. Glutamate release is inhibited.  D. Strong depolarization expels Mg2+ from the pore of the NMDA receptor channel.  E. The equilibrium potential for Ca2+ becomes less positive. Answers  Answers D. NMDA-receptor-dependent LTP is induced when sufficient depolarization is received postsynaptically, during the release of glutamate from the presynaptic terminal, so that Mg2+ is expelled from the pore of the NMDA receptor channel and substantial amounts of Ca2+ can then enter through the pore. The surge of Ca2+ activates various enzymes, including protein kinases, triggering cascades that result in a strengthening of that synapse. High-frequency stimulation of multiple presynaptic fibers usually is needed to cause enough depolarization and allow enough Ca2+ to enter to activate the protein kinases. Low-frequency stimulation allows a much smaller amount of Ca2+ to enter, which can selectively activate protein phosphatases to produce the opposite effect, reducing the strength of the synapse (termed long-term depression   Organization of the Nervous System (Prosensefalon) (Rombensefalon) Prof.Dr. Ramazan Bal  Enterin NS Prof.Dr. Ramazan Bal  Major levels of CNS function Spinal cord level  A conduit for signals from periphery to brain, or in the opposite direction  Also neuronal circuits in the cord can cause – (1) walking movements, – (2) reflexes that withdraw portions of the body from painful objects, – (3) reflexes that stiffen the legs to support the body against gravity, – (4) reflexes that control local blood vessels, GI movements, or urinary excretion.  Major levels of CNS function Lower brain (subcortical) level  Medulla, pons, mesencephalon, hypothalamus, thalamus, cerebellum &basal ganglia  Many of subconscious activities of the body are controlled in – Arterial pressure – Respiration, – Equilibrium, – Feeding reflexes, – Emotional patterns, Major levels of CNS function Higher brain (cortical) level  The cortex, for example, motor cortex, functions in association with lower CNS centers  Essential for most of thought processes