Signalling and receptors in the CNS Flashcards
Cell body
Contains the nucleus
Axon
Projection of nerve cell that transmits electrical impulses away from cell body to different neurones, muscles and glands.
Myelin sheath
surrounds the axon forming an electrically insulating layer, essential for functioning of the nervous system as it prevents loss of the electrical signal from an action potential
Dendrites
Extensions from neurones that receive chemical messages from other neurones
Synapse
Gap between the axon ending and the dendrite of the next neurone
Depolarisation
excitation of neurone (by making membrane potential more positive)
Hyperpolarisation
inhibition of neuronal activity (by making membrane potential more negative), occurs due to excess K+ efflux out of the neurone
Action potential
- Na+ channels open, making inside more positive
- Closing of Na+ channels
- Opening of K+ channels, making inside more negatively charged
Action potentials are generated in the
presynaptic neurone
Action potentials travel down the
axon to the nerve terminal
Action potentials are always
excitatory - it is the responses they evoke in the post-synaptic cell that can be eitherbe excitatory or inhibitory
Signalling between neurones
must be chemical
Neurotransmitter
A chemical that binds to a receptor, causing a biochemical or electrical response
released by presynaptic terminals and produce rapid excitatory or inhibitory responses in postsynaptic neurones
How do action potentials lead to neurotransmitter release
- action potentials arrive at axon terminal
- voltage-gated Ca2+ channels open
- Ca2+ enters cell
- Ca2+ signals to vesicles
- vesicles move to the membrane
- docked vesicles release neurotransmitter by exocytosis
- neurotransmitter diffuses across synaptic cleft and binds to receptors
Excitatory and inhibitory post-synaptic potentials (EPSPs and IPSPs)
summate to determine the likelihood of the post-synaptic neurone producing an action potential
Neuronal network
allows for multiple inputs to the postsynaptic neurone producing an additive effect, making it more likely the threshold for an action potential will be reached
Glial cells
support neurones
Astrocytes
maintain brain homeostasis by maintaining nutrition and regulating ion concentrations
-regulate the external chemical environment of neurones by removing excess potassium ions.
-play a role in neurotransmitter synthesis and metabolism
-participate actively in chemical signalling, functioning essentially as ‘inexcitable neurones’
Oligodendrocytes
produce myelin, each forms one segment of myelin for several adjacent axons
Microglia
act like macrophages, scavenging unwanted materials from the brain
proliferate in disease states
Blood brain barrier
composed of astrocytes, neurones and endothelial cells, acting as a physical separation from the rest of the body
blood brain barrier penetration is a key factor in CNS pharmacology
Fast neurotransmitters
operate mainly through ligand-gated ion channels
Slow neurotransmitters and neuromodulators
operate mainly through G protein-coupled receptors (GPCRs)
Dopamine
catecholamine, principally inhibitory
found in high concentrations at basal ganglia
involved in motor control
Serotonin
monoamine 5-hydroxytryptamine (5-HT) found in many non-neuronal cells and in peripheral nervous system
actions mostly inhibitory
effects on a wide range of physiological and behavioural processes (e.g. sleep, mood, sensory transmission, feeding). It also mediates the hallucinogenic properties of many psychoactive drugs
GABA
amino acid that is the principal inhibitory neurotransmitter in the mammalian CNS
produced by the decarboxylation of glutamate, and is found in high concentrations and almost exclusively in the brain.
Glutamate
L-Glutamate is the principal and ubiquitous excitatory transmitter in the central nervous system
Glutamate is involved in cognitive functions such as learning and memory in the brain
Most abundant neurotransmitter in the vertebrate nervous system
Acetylcholine
excitatory transmitter in the central nervous system
brain contains a number of cholinergic areas, each with distinct functions. They play an important role in attention, memory and motivation.
Schizophrenia, psychoses
abnormalities of dopaminergic neurotransmission
Depression, affective disorders
abnormalities of serotonergic (and NA) neurotransmission
Epilepsy
abnormal spread of electrical activity: involvement of GABAergic or glutamatergic neurotransmission
Parkinson’s disease
Degenerative loss of dopaminergic neurotransmission
Alzheimer’s disease
degenerative loss of cholinergic neurotransmission
Ionotropic receptors
ligand-gated ion channels - fast activation
NT binds as agonist, opens ion channel leading to hyperpolarisation or depolarisation
e.g. nicotinic ACh receptor
Metabotropic receptors
G-protein-coupled receptors - slow activation
NT binds leading to activation of ion channels and second messenger cascade
e.g. muscarinic ACh receptor
Noradrenaline receptors
⍺ and β subtypes
⍺
more sensitive to noradrenaline
constrict blood vessels, increasing blood pressure
cause bronchoconstriction in lungs
β
more sensitive to adrenaline
β1
increases heart rate
β2
increases bronchodilation
Ligand-gated ion channel
contains integral ion channel (cationic or anionic)
4-5 protein subunits (transmembrane domains)
second transmembrane domain fully transverses membrane and forms the pore - provides specificity to specific ions
Examples of ligand-gated ion channels
acetylcholine (nicotinic)
glutamate (NMDA)
5HT3
GABAA
G-protein coupled receptors
Intracellular effects via activation of G-protein
ligand binds in the middle of 7 transmembrane domains
GPCR activation
NT binding to G protein leads to activation or inhibition of second messenger
second messenger activates secondary effectors such as protein kinases or ion channels
further steps may include activation of transcription factors (e.g. CREB) - enter the nucleus and activate gene expression
Adenylyl cyclase-cAMP
- signal molecule binds to GPCR which activates G protein
- G proein turns on adenylyl cyclase
- adenylyl cyclase converts ATP to cyclic AMP
- cAMP activates protein kinase A
- protein kinase A phosphorylates other proteins leading to a cellular response
Drug targets at the synapse
Ion channels/transmitter release
Receptors
Enzymes
Transporters
Ion channel blockers - local anaesthetics
Lidocaine blocks the fast voltage-gated Na+channels responsible for depolarisation at the synapse. → electrical impulse is stopped in its tracks
Postsynaptic neuron will not depolarize and will thus fail to transmit anaction potential.
This creates the anaesthetic effect by stopping pain signals
Receptor agonists or antagonists
Inhibits neurotransmitter release from pre-synaptic neurone
or
inhibits neurotransmitter binding to post-synaptic receptors
Dopamine receptor antagonist - haloperidol
D2 antagonist - inhibits binding of dopamine to D2 receptors
Breakdown and metabolism of neurotransmitters
The action of acetylcholine is terminated by enzymatic degradation (acetylcholinesterase in the synapse)
Other enzymes are involved in the synthesis and breakdown of neurotransmitters within neurones
Reuptake (transport) or neurotransmitters
The action of most neurotransmitters is controlled by reuptake systems, sited on neurones and glia
Transporter proteins (“uptake” systems) in the plasma membrane take up transmitters, utilizing ion gradients (e.g. Na+, Cl-)
Reuptake inhibitors
e.g. tricyclic antidepressants
target neurotransmitter reuptake
bock transporters expressed at the synapse preventing uptake of neurotransmitter so more is available
Inhibition of neurotransmitter metabolising enzymes
e.g. anticholinesterases
symptomatic therapy for Alzheimer’s disease (not neuroprotective
anti-cholinesterase is a chemical or a drug that inhibits the acetylcholinesterase enzyme from breaking down acetylcholine, thereby increasing both the level and duration of action of the neurotransmitter acetylcholine
