TRANSDUKSI SINYAL, SYNAPS DAN NEUROTRANSMITTER PDF

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TRANSDUKSI SINYAL, SYNAPS DAN NEUROTRANSMITTER Rahmatina B. Herman Fakultas Kedokteran - Unand Neuron Neuron is basic functional unit of nervous system Central nervous system contains > 100 billion neurons Neuron is composed of 3 major parts: - Soma : main body of neuron - Axon : a single project...

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TRANSDUKSI SINYAL, SYNAPS DAN NEUROTRANSMITTER Rahmatina B. Herman Fakultas Kedokteran - Unand

Neuron Neuron is basic functional unit of nervous system Central nervous system contains > 100 billion neurons Neuron is composed of 3 major parts: - Soma - Axon

: main body of neuron : a single projection from soma into a peripheral nerve - Dendrite : great numbers of branching projections, extend 1 mm into surrounding areas

The output signal travels by way of axon leaving the neuron, then has many separate branches to other parts of nervous system or peripheral body Incoming signals enter the neuron through dendrites

Structure of a large neuron in brain

Typical anterior motor neuron

Myelinated fiber

Neu o ….. Neuron generally has 4 important functional zones: 1. A receptor or dendritic zone, where multiple local potential changes generated by synaptic connections are integrated 2. A site where propagated action potentials are generated, that is in initial segment of neurons or initial node of Ranvier 3. An axonal process that transmits propagated impulses to nerve endings 4. The nerve endings, where action potentials cause the release of synaptic transmitters

Neu o ….. The axons of many neurons are myelinated, and some are unmyelinated The myelin sheath envelops the axon except at its ending and at nodes of Ranvier In central nervous system (CNS) most neurons are myelinated Lost of myelin (such as in multiple sclerosis) is associated with delayed or blocked conduction in the demyelinated axons

Axonal Transport Neurons produce and secret transmitter, and secretory zone is at the end of axon Proteins and polypeptides are synthesized in cell body, and tranported to axonal terminals by axoplasmic flow (orthograde transport) Synaptic vesicles recycle in membrane, but some used vesicles are carried back to cell body (retrograde transport) and deposited in lysosomes Some materials taken up at terminal by endocytosis, including nerve growth factor (NGF) are also transported back to cell body

Axonal transport along microtubules by dynein and kinesin

EXCITATION AND CONDUCTION

Basic Physics of Membrane Potential Ion concentration difference on the 2 sides of cell e a e → diffusion → diffusio pote tial

Basi Ph si s of Me

a e Pote tial…..

Sodium-Potassium (Na+-K+) pu p → active transport

Feedback Control ion Channels

Positive feedback

Feed a k Co t ol io Cha

Negative feedback

els…..

Nerve Action Potential Neurons have a low threshold for excitation Nerve signals are transmitted by action potentials Action potentials are rapid changes in membrane potential that spread rapidly along nerve fiber membrane Each action potential begins with a sudden change from normal resting negative membrane potential to positive potential and then ends with almost equally rapid change back to negative potential To conduct a nerve signal, the action potential moves alo g the e e fi e u til it o es to the fi e ’s end/terminal

Ne e A tio Pote tial….. The successive stages of action potentials are: Resting stage (polarization): - Membrane potential before action potential begins

Depolarization stage: - Membrane suddenly becomes very permeable to Na+, allowing tremendous number of positively charged Na ions to diffuse to interior axon - May cause overshoot beyond zero level

Repolarization stage: - Soon then Na channels begin to close and K channels ope → apid diffusio of K+ to e te io → e-establishes normal negative resting membrane potential

hyperpolarization

The changes in membrane potential (mV) and relative membrane permeability To Na+ and K+ during an action potential

Threshold Intensity Threshold intensity is minimal intensity of stimulating current that acting for a given duration will produce an action potential Threshold intensity varies with duration; with weak stimuli it is long and with strong stimuli it is short Slowly rising currents fail to fire the nerve because the nerve adapts to the applied stimulus, this process is called adaptation

Once threshold intensity is reached, a full-fledged action potential is produced

Propagation of Action Potential An action potential elicited at any point on an excitable e a e → e ites adja e t po tio s of e a e Direction of propagation: Action potential travels in all directions away from stimulus

All-or-Nothing principle: Once an action potential has been elicited at any point on membrane → - the depolarization process travels over the entire membrane if conditions are right; or - the depolarization process does not travel at all if conditions are not right

Propagation of action potentials in both directions

Electronic Potential and Firing Level Although subthreshold stimuli do not produce an action potential, but still have effect on membrane potential → localized depolarizing potential change that rises sharply and decays exponentially with time. The magnitude will drops off rapidly as distance between stimulating is increased. Anodal current produces a hyperpolarizing potential change of similar duration

These potential changes are called electronic potentials If the firing level ea hed → a a tio pote tial o u s

Electronic potentials and local response

Signal Transmission in Nerve Fiber Unmyelinated fiber: small fibers Myelinated fiber: large fibers

Saltatory conduction: conduction from node of Ranvier to node of Ranvier - No ions can flow through the thick myelin sheaths of myelinated fiber - Ions can flow with ease through the nodes of Ranvier → a tio pote tials a e o du ted f o ode to node

Saltatory conduction

SYNAPSE

Physiologic Anatomy of Synapse Synapse is the junction point from one neuron to the next

10,000-20,000 presynaptic terminals (minute synaptic knob) lie on surfaces of: - dendrites : 80-95%, and - soma : 5-20% Presynaptic terminals are the ends of nerve fibrils that originate from many other neurons

Incoming signals enter the neuron through synapses located on the neuronal dendrites and on cell body

Type of Synapses 1. Chemical synapse - The first neuron secretes at its nerve ending chemical substance, neurotransmitter, which in turn acts on receptor proteins in membrane of the next neuron to excite it; or inhibit it; or modify its sensitivity - O e- a o du tio at chemical synapses Signals always be transmitted from presynaptic neuron that secretes neurotransmitter to postsynaptic neuron on which neurotransmitter acts → sig als a e di e ted to a d spe ifi goals

T pe of “ apses….. 2. Electrical synapse - Characterized by direct open fluid channels that conduct electricity from one neuron to the next - Often transmit signals in either direction

- Most of these consist of small protein tubular structures: gap junctions, that allow free movement of ions from the anterior of one neuron to the next - By way of gap junctions that action potentials are transmitted from one smooth muscle fiber to the next, and from one cardiac muscle cell to the next

Information Transmission Through Synapse Information is transmitted in nervous system mainly in the form of nerve action potentials / nerve impulses Each impulse in its transmission may be: - facilitated or blocked from one neuron to the next; or - changed from a single impulse into repetitive impulses; or - integrated with impulses from other neurons to cause highly intricate patterns of impulses in successive neurons

I fo

atio T a s issio Th ough “ apse…..

Synapses determine the directions that the nervous signals will spread through nervous system

Some synapses transmit signals from one neuron to the next with ease, whereas others with difficulty Facilitatory and inhibitory signals from other areas in nervous system can control synaptic transmission Sometimes opening for transmission, sometimes closing

Some postsynaptic neurons respond with large numbers of output impulses, others respond with only few

Synaptic Functions in Memory Each time certain types of sensory signals pass through sequences of synapses, then: - The synapses become more capable of transmitting the same type of signal the next time (facilitation) - After the large number of times sensory signals passed th ough → the s apses e o e so facilitated - The synapses can also cause transmission of impulses through the same sequences of synapses even when the sensory input is not excited → a perception of experiencing the original sensations, although the perceptions are only memories of the sensations Precise mechanisms by which long-term facilitation of synapses occurs in the memory process are not known

Presynaptic Terminals Presynaptic terminal is separated from postsynaptic neuronal by synaptic cleft, width of 200-300 angstroms There are 2 internal structures important to function of synapse:

- Transmitter vesicles contain neurotransmitter, which will be released into synaptic cleft and in turn will either excites or inhibits postsynaptic neuron - Mitochondria provide ATP which in turn supplies energy for synthesizing new neurotransmitter

P es apti Te

i als…..

When an action potential spreads over a presynaptic terminal, depolarization of its membrane causes a small number of vesicles to empty neurotransmitter into the cleft The released neurotransmitter → i ediate change in permeability characteristics of the postsynaptic eu o al e a e → excitation or inhibition of the postsynaptic neuron, depending on neuronal receptor characteristic

Transmitter Releasing Mechanisms Presynaptic membrane contains large numbers of voltage-gated calcium channels When action potential depolarizes presynaptic e a e → Ca ha els ope → la ge u e s of Ca ions flow into presynaptic terminal Ca ions then bind with special protein molecules on the elease sites of p es apti e a e→ elease sites ope → eu ot a s itte eleased from vesicles into synaptic cleft

Transmitter Action on Postsynaptic Neuron Postsynaptic membrane contains large number of receptor proteins which have 2 important components: 1. Binding component 2. Ionophore component: - ion channel: > cation channel, or > anion channel - second messenger activator to increase or decrease specific cellular function

T a s itte A tio o Posts apti Neu o ….. Cation channel: - Most often allowing Na ions to pass, also K ions a d/o Ca io s → e ite the eu o - Transmitter that opens cation channels is excitatory transmitter

Anion channels: - Allowing mainly Cl ions to pass, and minute ua tities of othe a io → i hi it the eu o - Transmitter that opens anion channels is inhibitory transmitter

Physiologic anatomy of synapse

Second Messenger System in Postsynaptic Neuron In the process of memory, require prolonged changes in neuron for seconds-months after initial transmitter substance is gone Second messenger causes prolonged effect as follow: - The ion channels are not suitable for causing prolonged postsynaptic neuronal changes because the channels close within milliseconds after transmitter substance is no longer present - Prolonged postsynaptic neuronal excitation or inhibition is achieved by activating a second messenger inside postsynaptic neuronal cell itself

“e o d Messe ge “ ste

i Posts apti Neu o …..

One of most common types of second messenger systems uses a group of proteins called G-proteins G-protein is attached to the portion of receptor that protrudes into the interior of cell G-protein consists of 3 components: - alpha (α): activator portion of G-protein - beta (β) and gamma (ϒ) are attached to α and also to the inside of cell membrane adjacent to receptor protein

On activation by a nerve impulse, α portion separates from β and ϒ → α then is free to move within cytoplasm of cell

“e o d Messe ge “ ste

i Posts apti Neu o …..

The free α performs one or more multi functions depending on specific characteristic of neuron type The free α will allow 4 changes to be occurred: 1. Opening specific ion channels through postsynaptic cell and stay open for a prolonged time 2. Activation of cAMP or cGMP which activate highly spe ifi eta oli a hi e i eu o → lo g-term ha ges i ell st u tu e → lo g-term excitability of neuron 3. Activation of one or more intracellular enzymes → specific chemical functions in cell 4. Activation of gene transcription → fo atio of e p otei s ithi eu o → changing its metabolic machinery or its structure

Possible effects of G-protein

Mechanism of Excitation in Excitatory Receptors 1. Opening of Na channels → positi e ele t i al ha ges flo to i side of posts apti eu o → pote tial e a e↑→ excitatory 2. Depressed conduction through: - Cl ha els → diffusio of egati el ha ged to i side ↓ - K ha els → diffusio of positi el ha ged to outside ↓ 3. Various changes in internal metabolism of postsynaptic neuron to excite cell activity eg. - the u e of e itato e a e e epto s ↑, o - the u e of i hi ito e a e e epto s ↓ “o, esti g e a e pote tial of posts apti ↑ a o e resting or depolarization, and this membrane potential is called excitatory postsynaptic potential (EPSP)

Mechanism of Inhibition in Inhibitory Receptors 1. Opening of Cl channels → egati e ele t i al ha ges flo to i side of posts apti eu o → egati it i side ↑ → inhibitory 2. Conductance of K ions out of posts apti eu o ↑ → diffusio of positi e io s to e te io ↑ → egati it i side ↑ → i hi ito 3. Activation of receptor enzymes that inhibit cellular metabolic functions: - the u e of i hi ito e a e e epto s ↑, o - the u e of e itato e a e e epto s ↓ “o, esti g e a e pote tial of posts apti ↓, e o e more negative or hyperpolarization, and this membrane potential is called inhibitory postsynaptic potential (IPSP)

Special Characteristics of Synaptic Transmission Fatigue of synaptic transmission - When excitatory synapses are repetitively stimulated at

a apid ate → the u e of dis ha ges posts apti neuron is very great at first, but the firing rate becomes progressively less in succeeding milliseconds or seconds - The development of fatigue is a protective mechanism against excess neuronal activity - The mechanism of fatigue is: > mainly exhaustion of the stores of transmitter substance in presynaptic terminals > progressive inactivation of many of postsynaptic membrane receptors > slow development of abnormal concentrations of ions inside postsynaptic neuron

“pe ial Cha a te isti s of “ apti T a s issio ….. Synaptic delay Due to during signal transmission from presynaptic to postsynaptic required certain amount of tome for: 1. Discharge of transmitter by presynaptic terminals 2. Diffusion of transmitter to postsynaptic neuron membrane 3. Action of transmitter on membrane receptor of postsynaptic 4. Action of receptor to increase membrane permeability 5. Inward diffusion of Na ion to raise the excitatory postsynaptic potential to a high enough level to elicit action potential

The minimal period of time required is ± 0.5 millisecond

“pe ial Cha a te isti s of “ apti T a s issio ….. Effect of changes in pH on synaptic transmission:

- Alkalosis: ↑↑ eu o al e ita ilit → e e al epilepti seizures attack - Acidosis: ↓↓ eu o al a ti it → a auses o a

Effect of oxygen supply on synaptic transmission: - Hypoxia:

fo o l a fe se o ds → o plete i e ita ilit of so e eu o s → u o s ious

Effect of drugs on synaptic transmission:

- Caffei e, theoph lli e, theo o i e ↑ eu o al e ita ilit ↓ th eshold fo e itatio , su h as - “t h i e ↑ eu o al e ita ilit ↓↓ i hi ito t a s itte su sta es → se e e to i us le spas s - A estheti d ug ↑ eu o al th eshold fo e itatio → ↓ s apti t a s issio

NEUROTRANSMITTER

Type of Transmitter Small molecule

Neuropeptides

Rapidl a ti g → a ute responses Transmission of sensory sig als → ai → oto signals back

More prolonged actions

Long-term changes in numbers of neuronal receptors, long-term opening or closure of certain ion channels, longterm changes in numbers of synapses or size of synapses

Small Molecule Synthesized in cytosol of presynaptic terminal and are absorbed by active transport into many transmitter vesicles in terminal If action potential ea hes p es apti te i al → transmitter released into synaptic cleft → a t o posts apti eu o The vesicles that store and release small-molecule transmitters are continually recycled and used over and over again After vesicles fuse with synaptic membrane and open to release transmitter, vesicle membrane becomes part of synaptic membrane Within seconds-minutes vesicle portion of membrane invaginates back to inside of presynaptic terminal and pinches off to form a new vesicle The new vesicular membrane still contains appropriate enzyme proteins or transport proteins required for synthesizing and/or concentrating new transmitter inside vesicle

Some of Small-Molecule Transmitter Acetylcholine - Secreted by neurons especially: > terminals of large pyramidal cells from motor cortex > neuron in basal ganglia > motor neurons that innervate skeletal muscles > preganglionic neuron of autonomic nervous system > postganglionic of parasympathetic nervous system > some of postganglionic sympathetic nervous system - Most ACh has excitatory effect, however it has inhibitory effects at some peripheral parasympathetic nerve endings such as inhibition of heart by nervus vagus

Some of Small-Mole ule T a s itte ….. Norepinephrine - Secreted by terminals of many neurons whose cell bodies are located in brain stem and hypothalamus - Specifically NE secreting neurons located in locus cereleus in pons send nerve fibers to widespread areas of brain to help control overall activity and mood of mind, such as increasing level of wakefulness - In most of these areas, NE probably activates excitatory receptors, but in a few area it activates inhibitory receptors - NE is also secreted by most postganglionic neurons of sympathetic nervous system

Some of Small-Mole ule T a s itte ….. Dopamine - Secreted by neurons that originate in substantia nigra - Effect of dopamine is usually inhibition

Glycine - Secreted mainly at synapses in spinal cord - It is believed to always act as an inhibitory transmitter

GABA (gamma-aminobutyric acid) - Secreted by nerve terminals in spinal cord, cerebellum, basal ganglia, and many areas of cortex - It is believed always to cause inhibition

Some of Small-Mole ule T a s itte ….. Glutamate - Secreted by presynaptic terminals in many of sensory pathways entering CNS, in many areas of cerebral cortex - Probably always causes excitation

Serotonin - Secreted by nuclei that originate in brain stem and project to many areas in brain and spinal cord, especially to dorsal horns of spinal cord and to hypothalamus - Acts as an inhibitor of pain pathways in spinal cord - Inhibitor action in higher regions of nervous system is believed to help control mood, perhaps to cause sleep

Some of Small-Mole ule T a s itte ….. Nitric oxide - Secreted by nerve terminals in areas of brain responsible for long-term behavior ...