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Discovery of chemical messengers

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- 1921 - Otto Loewi - acetylcholine and adrenaline (epinephrine) - Frog hearts

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Accelerates the heartbeat in amphibians

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Adrenaline

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Accelerates the heartbeat in mammals

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Noradrenaline (norepinephrine)

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Acetylcholine

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- motor system stimulant - slows heartbeat through release by vagus nerve (atropine blocks ACh)

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Manufacturing of Neurotransmitters

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- Axon terminal from building blocks from food - Cell body according to instructions from DNA - Axon Terminal from mRNA from nucleus

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4 steps in process of transmitting info across chemical synapse

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Transmitter must be... 1. synthesized and stored in axon terminal 2. transported to presynaptic membrane and released in response to action potential 3. interact with the receptors on membrane of target cell located on the other side of the synapse 4. somehow be inactivated or it would continue to work indefinitely

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Neurotransmitter release

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- Presynaptic membrane is rich in voltage-sensitive calcium channels, and the surrounding extracellular fluid is rich in Ca2+. - The action potential opens these voltage-sensitive calcium channels, allowing an influx of calcium ions into the axon terminal. - The incoming Ca2+ binds to a chemical called calmodulin, and does two chemical actions

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Two things that can happen after Ca2+ binds to calmodulin

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- releases vesicles bound to the presynaptic membrane - releases vesicles bound to filaments in the axon terminal.

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How is the postsynaptic cell affected

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The transmitter may... - Depolarize the postsynaptic membrane and so have an excitatory action on the postsynaptic cell - Hyperpolarize the postsynaptic membrane and so have an inhibitory action on the postsynaptic cell - Initiate other chemical reactions.

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Autoreceptors

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- (self-receptors)- presynaptic receptors that a neurotransmitter may activate. - Axon terminal provide feedback to itself

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What determines excitatory/inhibitory?

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The receptor

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Removal of a neurotransmitter

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- Diffuses away from the synaptic cleft and is no longer available to bind to receptors. - Inactivated or degraded by enzymes in the synaptic cleft. - Taken back into the presynaptic axon terminal for subsequent reuse, or the by-products of degradation by enzymes may be taken back into the terminal to be used again in the cell. - The protein molecule that accomplishes this reuptake is a membrane pump called a transporter. - Taken up by neighboring glial cells, which may contain enzymes that degrade transmitters.

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Type I synapse

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- Excitatory - Typically located on dendrites - Round vesicles - Dense material on membranes - Wide cleft - Large active zone

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Type II Synapse

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- Inhibitory - Typically located on cell body - Flat vesicles - Sparse material on membranes - Narrow cleft - Small active zone

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If a cell is normally inhibited how can an action potential be generated

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if the cell body's inhibition is reduced

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Ionotropic receptors

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- allow the movement of ions across a membrane - two parts: (1) a binding site for a neurotransmitter and (2) a pore or channel - Fast response

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Metabotropic receptor

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- lacks its own pore but has a binding site for a neurotransmitter. - produce changes in nearby ion channels or bring changes in the cell's metabolic activity - the receptor is associated with one of a family of proteins called guanyl nucleotide-binding proteins, or G proteins for short - Slow response

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Acetylcholine

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- excitatory effect on skeletal muscles, where it activates an ionotropic receptor, - inhibitory effect on the heart, where it activates a metabotropic receptor.

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Three groups of transmitters based on their composition

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- Small-molecule transmitters - Peptide transmitters (also called neuropeptides) - Transmitter gases

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Small-molecule transmitters

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- synthesized and packaged for use in axon terminals. - can be quickly replaced at the presynaptic membrane. - main components are derived from the food that we eat. - Include: acetylcholine, dopamine, norepinephrine, epinephrine, serotonin, glutamate, GABA, glycine, and histamine

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Acetylcholine (Ach)

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- Involved with the parasympathetic nervous system (slows heart for rest) - Released at neuromuscular junction affecting the skeletal musculature throughout the body - distributed throughout the brain - Affects learning and memory

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Acetylcholine is made up of what two parts?

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choline and acetate

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Choline

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substance obtained from the breakdown of fats, such as egg yolk, and acetate is a compound found in such substances such as vinegar.

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acetyl coenzyme A (acetyl CoA)

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one enzyme that carries acetate to the site where the transmitter is synthesized

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choline acetyltransferase (ChAT)

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second enzyme that transfers acetate to choline to form acetylcholine (ACh).

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acetylcholinesterase (AChE)

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third enzyme that reverses the process of synthesis, detaching acetate from choline.

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Catecholamines

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- Group of 3 different amine NT that contain catechol: Dopamine, Norepinephrine, Epinephrine - Share a catechol nucleus and a common biosynthetic pathway where enzymes are added to shape the raw materials to produce the needed NT - Neurotransmission is similar to processes for other transmitter systems, but they can sometimes be released through the dendrite in a nonexocytotic pattern

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epinephrine process

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see powerpoint

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Catecholamines

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- Widely distributed: - DA- Forebrain, cortical regions, limbic system - Related to ADHD, Parkinson's Disease - NE- Brain stem, influencing the thalamus, hypothalamus, limbic system and cortex - Associated with stress-related disorders, Depression

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Serotonin (5-HT)

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- 5-Hydroxytryptamine - Major neurotransmitter involved in mood, aggression and appetite regulation - Tryptophan - Synthesis - • Reuptake and enzymatic degradation inactivate excess serotonin after discharge and receptor binding - Concentration in cell bodies in brainstem area- raphe nuclei - Send projections to many parts of the brain

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Tryptophan (Serotonin)

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Amino acid from which the neurotransmitter serotonin is derived, the availability of this in the extracellular fluid of neurons regulates the synthesis of serotonin

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Synthesis (Serotonin)

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Tryptophan collected in CNS circulatory systemà transformed into 5-Hydroxytryptophan (5-HTP) by enzyme tryptophan hydroxylase à aromatic amino acid decarboxylase (AADC) metabolizes 5-HTP into 5-HT

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Influence of Serotonin

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- body temperature, respiration, blood pressure, hormone release, uterine activities, attention and arousal, food intake, mood, aggression, nociception and sleep and dreaming

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5-Hydroxyindole acetic acid (5-HIAA)

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Metabolic break-down product of serotonin found in the cerebrospinal fluid, main metabolite of serotonin

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Amino Acid Transmitters Excitatory amino acid: Glutamate (Glu)

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- Principle excitatory neurotransmitter in the brain - Regulates cortical and subcortical functions- cognitive activities - Overexcitation of NMDA receptors leads to neurotoxicity (neural damage due to some threat presented to the nervous tissue such as toxins, low oxygen, decreased glucose, etc.)

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After release of glutamate, activates receptors

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- Ionotropic: Nmethyl-D-aspartate (NMDA), Kainate, Alpha-amino hydroxy-methyl-isoxazolepropionate (AMPA) - Metabotropic: metabotropic-1 and -2

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Amino Acid Transmitters Inhibitory amino acids

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- GABA- principle inhibitory transmitter in the brain - GABA releasedà binds to GABA-A receptorà Cl‾ ion channels openà hyperpolarization of the neuron occursà makes it harder for neuron to fire - GABA that is released and left over is taken up by neighboring neurons and glia - high concentartion in cortex - can regulate seizure activity

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Formation of GABA

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a simple modification of glutamate

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Glycine (Gly)

answer

Major inhibitory NT for brainstem, spinal cord, and retina

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