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

• A junction that mediates information transfer from one neuron:– To another neuron

• Called neuro-synapses or just synapse

– To an effector cell• Neuromuscular synapse if muscle involved• Neuroglandular synapse if gland involve

• Presynaptic neuron – conducts impulses toward the synapse

• Postsynaptic neuron – transmits impulses away from the synapse

• Two major types:– Electrical synapses– Chemical synapses

Synapses

Synapses

Figure 11.17

1. Axodendritic synapse2. Axosomatic synapse3. Axoaxonic synapse

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.

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

Chemical SynapseEvents at a chemical synapse1. Arrival of action potential on

presynaptic neuron opens volage-gated Ca++ channels.

2. Ca++ influx into presynaptic term.3. Ca++ acts as intracellular messenger stimulating synaptic vesicles to fuse

with membrane and release NT via

exocytosis.4. Ca++ removed from synaptic knob by mitochondria or calcium-pumps.5. NT diffuses across synaptic cleft and binds to receptor on postsynaptic

membran6. Receptor changes shape of ion

channel opening it and changing membrane

potential7. NT is quickly destroyed by enzymes

or taken back up by astrocytes or

presynaptic membrane.Note: For each nerve impulse reaching

the presynaptic terminal, about 300 vesicles are emptied into the cleft. Each vesicle contains about 3000 molecules.

Removal of Neurotransmitter from Synaptic Cleft

• Method depends on neurotransmitter

• ACh: acetylcholinesterase splits ACh into acetic acid and choline. Choline recycled within presynaptic neuron.• Norepinephrine: recycled within presynaptic neuron or diffuses away from synapse. Enzyme is monoamine oxidase (MAO). Absorbed into circulation, broken down in liver.

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

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.

• 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

• 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

• 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

• 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

Summation

Figure 11.21

• 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

• 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

• 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

Channel-Linked Receptors

Figure 11.23a

• 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

• 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

G Protein-Linked Receptors: Mechanism

Figure 11.23b

• 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

• Acetylcholine (ACh)• Biogenic amines• Amino acids• Peptides• Novel messengers: ATP and

dissolved gases NO and CO

Chemical Neurotransmitters

• 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

Comparison of Somatic and Autonomic Systems

Figure 14.2

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

Acetylcholine

• 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.

• 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

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

Figure 11.22

BIOGENIC AMINES: Norepinephrine

• 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

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

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

• Include:– GABA – Gamma ()-aminobutyric acid – Glycine– Aspartate– Glutamate

• Found only in the CNS

Neurotransmitters: Amino Acids

Amino Acid Neurotransmitters

• Excitatory Amino Acids1. 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!)

Amino AcidsInhibitory Amino Acids1. GABA (Gamma aminobutyric acid)• Direct or indirect action (depending on type of

receptor• Main inhibitory neurotransmitter in the brain

- Selectively permeable to Cl- (hyperpolarizes memb.)

• Cerebral cortex, cerebellum, interneurons throughout brain and spinal cord

• Inhibitory effects augmented by alcohol and benzodiazepines (antianxiety drugs like Valium and Librium) and barbiturates - these drugs increase the number of GABA

receptors and thus enhance the inhibitory activity of GABA

• Decreased GABA inhibition amy lead to epilepsy

• 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

• 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

• Two classifications: excitatory and inhibitory– Excitatory neurotransmitters cause

depolarizations (e.g., glutamate)– Inhibitory neurotransmitters cause

hyperpolarizations (e.g., GABA)

Functional Classification of Neurotransmitters

• 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