OPT 112 Neurotransmitters; G Proteins

Neurotransmitters

chemical messengers that cross the synaptic gaps between neurons

excitatory neurotransmitters

lower postsynaptic membrane potential to increase firing of EPSPs

Examples of excitatory neurotransmitters

glutamate, aspartate, acetylcholine

inhibitory neurotransmitters

actions will stabilize or raise the postsynaptic potential to decrease firing rate (IPSPs)

Examples of inhibitory neurotransmitters

gamma aminobutyric acid (GABA) and glycine

What neurotransmitters can be both IPSPs and EPSPs

dopamine depending on neuron location

Neuromodulation

release of chemicals from one cell that alter or regulate the reponse of neurons to neurotransmitters

allosteric regulation

The binding of a regulatory molecule to a protein at one site that affects the function of the protein at a different site.

Agonist

modulator mimics action of neurotransmitter by binding to the receptor

Antagonist

modulator blocks action of neurotransmitter by binding to the receptor

facilitation

modulator enhances effect of neurotransmitter by its increased concentration in synaptic cleft, slower degradation, slower reuptake

inhibition

reduces effect of neurotransmitter by decreased concentration in synaptic cleft, faster degradation, faster reuptake

Neurotransmitters can be classified based on

structure and function

ionotropic receptors

receptors that are coupled to ion channels and affect the neuron by causing those channels to open

metabotropic receptors

receptors that are associated with signal proteins and G proteins

Acetylcholine (ACh)

A neurotransmitter that enables learning and memory and also triggers muscle contraction

biogenic amines

- modified amino acids

List the catecholamines

dopamine, norepinephrine, epinephrine, synthesized by tyrosine

Indolamines examples

serotonin and histamine (synthesized by tryptophan and histidine)

amino acids

include glutamate, glycine, aspartate, and GABA

Neuropeptides

2-40 amino acids long, include endorphins as well as others relating to memory regulation and satiety and pain transmission to CNS

Where is acetylcholine found?

PNS and CNS

neurons utilizing ACh as primary neurotransmitter are called

cholinergic neurons

how to create ACh

choline acetyl transferase: acetyl coA + choline --> acetylcholine + CoA

What happens when botulism toxin binds to SNARE proteins?

prevents vesicle from releasing excitatory Ach

Where does degradation of Ach occur? what enzyme degrades it?

synaptic cleft, acetylcholinesterase

muscarinic receptors

found in CNS, autonomic effector (cardiac and smooth muscle) at its synapse with the postganglionic neuron of ANS

nicotinic receptors

somatic effector (skeletal muscle) at neuromuscular junctions in somatic nervous system. postganglionic neurons at synapse with preganglionic neurons in the autonomic ganglia of the ANS

Other than ACH degradation, what other ways can the neurotransmitter be removed from the synaptic cleft

-reuptake into presynaptic cell

-uptake by glial cells

- diffusion away from synaptic cleft

Neurons associated with ACh system degenerate in people with

alzheimers

what percentage of people over 85 are affected by alzheimers?

50%

Alzheimer's disease

decreased amount of ACh in certain areas of the brain and even the loss of postsynaptic neurons that would have responded to it

What are effects of alzheimers?

declining language and perceptual abilities, confusion and memory loss

Where are dopamine and norepinephrine commonly found?

neurons of hypothalamus and brainstem of the CNS (norepinephrine can be found in PNS)

Where is epinephrine synthesized?

adrenal medulla (adrenaline)

How are catecholamines degraded?

monoamine oxidase

MAO inhibitors

inhibit the action of an enzyme called MAO, which normally breaks down and deactivates norepinephrine and serotonin.

adrenergic receptors

receptor sites for the sympathetic neurotransmitters norepinephrine (CNS and PNS) and epinephrine (PNS)

G-coupled protein receptors

A type of receptor that can indirectly cause the opening or closing of ion channels; typically do not let ions pass through them

Alpha 1 receptors

smooth muscle contraction

Alpha 2 receptors

smooth muscle contraction and neurotransmitter inhibition

Beta 1 receptors

heart muscle contraction, smooth muscle relaxation, glycogenolysis

Preganglionic fibers of ANS

Cholinergic

postganglionic fibers in sympathetic division

mostly adrenergic; a few cholinergic

postganglionic fibers in parasympathetic division

cholinergic

Indolamines

serotonin (5-hydroxytryptamine) and histamine

what is serotonin derived from?

Tryptophan

where is serotonin found ?

majority of brain and spinal cord

What does serotonin do?

exerts excitatory effect muscle control and inhibitory effect on pathways that mediate sensation

when are serotonin levels lowest? highest?

during sleep, during alertness

SRI (Serotonin Reuptake Inhibitor)

aid in management of depression (paxil)

functions of seratonin

regulating sleep, emotions, regulate cell growth, vascular smooth muscle contraction

What three neurotransmitters serve to regulate cognitive function, mood, and emotion?

serotonin, dopamine, noradrenaline

What is noradrenaline responsible for?

ergotrophic vigilance (energy expenditure), motivation, anxiety, irritability

what is dopamine responsible for?

please drive - motivation, appetite, sex, aggression

What causes Parkinson's disease?

loss of dopamine releasing neurons in substantia nigra of the midbrain

What are symptoms of parkinsons?

tremors, head nodding, pill rolling behaviors, bent walking posture, shuffling gait, still facial expressions, slow in initiating and executing movement

What drug manages parkinsons?

L-Dopa; alleviates symptoms and often combines with deprenyl which prevents its degradation

amino acid neurotransmitters

glutamate, aspartate, glycine, GABA

Glutamate

A major excitatory neurotransmitter; involved in memory (50% of all ESPS in CNS)

Where is glutamate synthesized?

mitochondria from glucose and glutamine

ionotropic glutamate receptors

learning and memory, AMPA, NMDA

AMPA receptor

fast EPSP, conduction of Na+, depolarizes the membrane

NMDA receptor

requires ampa first—bump Mg2+ channel allowing for influx of Ca2+

reuptake

glutamate is recycled by glial cells and converted to glutamine for reuptake by the presynaptic cell

Gamma-aminobutyric acid (GABA) --> GABA a, GABA b

most inhibitory neurotransmitter as it dampens neural activity in the brain

how does GABA alter the membrane potential?

binds to ion channel and shifts to more negative charge as Cl- channels are open ; generates IPSPs @ postsynaptic neuron

binding sites on GABA receptors serve as targets for

steroids, ethanol, and drugs including barbiturates and benzodiazepines

how is glycine formed?

converted from serine by an enzyme

Glycine

inhibitory neurotransmitter of the brainstem and spinal cord

how does glycine work?

cause IPSPs by increasing Cl- influx into postsynaptic cell , regulate skeletal muscle contractions

What is an antagonist for glycine?

neurotoxin strychnine ; causes hyper excitability through nervous system leading to convulsions and spastic contraction of skeletal muscles

examples of neuropeptides

insulin, glucagon, oxytocin, vasopressin

What is nitric oxide synthesized from?

Arginine

functions of nitric oxide

vasodilation, long term memory

What happens if too much nitric oxide is synthesized?

proinflammatory, cytotoxic

Endocannabinoids

decrease neurotransmitter release from presynaptic neurons altering memory and cognition as well as increase appetite

where are Endocannabinoids synthesized?

in post-synaptic terminals in response to Ca++ influx

Endocannabinoids examples

anandamide (AEA) and 2-arachidonyl-glycerol (2-AG) bind to CB1 and CB2

What are endocannabinoids present in

active ingredient in marijuana/THC

Ways in which a drug may effect neurotransmitters

see image

What is the most common effect drugs will have on neurotransmitters

inhibit or stimulate second messenger activity within postsynaptic cell

ACh

excitatory

precursor: choline +acetyl CoA

type of vesicle: small, clear

glutamate

excitatory

precursor: glutamine

type of vesicle: small, clear

GABA

inhibitory

precursor: glutamate

type of vesicle : small, clear

glycine

inhibitory

precursor: serine

type of vesicle: small, clear

epinephrine, norepinephrine, dopamine

excitatory

precursor: tyrosine

type of vesicle: small, dense core or large, and irregular

serotonin (5-HT)

mostly inhibitory

precursor: tryptophan

type of vesicle: large, dense core

histamine

excitatory

precursor: histidine

type of vesicle: large, dense core

ATP

excitatory

precursor: ADP

type of vesicle: small, clear

neuropeptides

excitatory and inhibitory

precursor: amino acids/protein synthesis

type of vesicle: large, dense core

Endocannabinoids

inhibits inhibition

precursor: membrane lipids

vesicle type: none

nitric oxide

excitatory and inhibitory

precursor: arginine

vesicle type: none

Why are G proteins so important?

important for vision, tear formation, aqueous humor formation, responsible for many biochemical pathways

many medications (60%) and various systemic diseases affect them

7 TM (horseman)

Class A-F; play important role in cell physiology and biochemistry, play an important role in medicine

What are 7 TM activated by

light, olfactory stimulants, peptides, hormones and neurotransmitters

A disease linked to 7-TM can be caused by

-non functional receptors

-constitutive activation

-changes in ligand binding specificity

first messenger

binds to transmembrane G Protein coupled receptor (metabotropic) and can illicit an excitatory or inhibitory response in the cell

guanosine triphosphate (GTP)

bumped off activated receptor and travels to another transmembrane protein on the intracellular side

adenylate cyclase

converts ATP to form cAMP

- second messenger activates enzymes triggering many physiological changes within the cell