synapses and neurotransmitters 2 Flashcards
what should a neurotransmitter be
-be present in presynaptic terminals
-be released in response to stimulation
-act on the postsynaptic neuron
-Blocking the neurotransmitter should prevent synaptic transmission
How do we experimentally determine if a molecule acts as a neurotransmitter
-Is it there?->immunostaining- for specific proteins at the pre-synaptic terminal
-Does the cell express enzymes to synthesise it, or transporter proteins to store it? ->immunostaining, in situ hybridisation
-Is it released? -> Collect fluid around neurons after stimulating them (this might be difficult!) – remember Loewi’s 1921 experiment
-Does it affect the postsynaptic cell? -> Test if the molecule mimics the effect of stimulating the presynaptic cell- if postsynaptic cell responds then there’s a good chance that that’s what the presynaptic vesicle is releasing
-Block the neurotransmitter? ->Apply drugs; delete genes encoding enzymes/transporters/receptors
what are the 3 types of neurotransmitters
-amino acids e.g. glutamate, GABA, glycine
-amines, e.g. acetylecholine, noroepinephrine
-peptides, e.g. opioids and endorphins
whats the different between amino acids and amines against peptides
-amino acids:
=small molecules (100-200Da)
=stored in synaptic vesicles
=can bind to ligand-gated ion channels or G-protein coupled receptors
peptides:
= large molecules (1000-3000 Da)
=stored in secretory granules
=Only bind to G-protein coupled receptors
-Neurons usually release only one kind of neurotransmitter, but some can release more than one
-Often peptide-releasing neurons also release a small molecule transmitter, called a ‘co-transmitter’
how do Ligand-gated ion channels work
-directly depolarise or hyperpolarise the postsynaptic cell
-ion channels specific to a certain ion
how do G-protein-coupled receptors
-more complex effects
-Multiple possible second messengers
-Second messengers allow amplification
-1 NT binds to the G protein- G protein effects several proteins
how does Convergence and divergence allow flexibility
-Each transmitter can activate multiple different receptors
-Each receptor can activate different downstream effectors
-Different transmitters or receptors can activate the same downstream effector
divergence explained
transmitter-> rec subtype 1-> effector system x
-> rec subtype 2-> effector system y
-> rec subtype 2-> effector system z
-amplification of a signal
convergence explained
transmitter A-> a rec->effector system
transmitter B-> b rec-> effector system
transmitter C-> c rec-> effector system
whats glutamate
-an AA so found in all neurons- not released from them all though
-Most common excitatory transmitter in CNS
-Amino acid, therefore, found in all neurons
-3 ionotropic glutamate receptor subtypes based on the drugs which act as selective agonists
-Action is terminated by selective uptake into presynaptic terminals and glia
-name based on what they target
what are AMPA receptors
-AMPA receptors mediate fast excitatory transmission
-Glutamate binding to AMPA receptors triggers Na+ and K+ currents resulting in an EPSP
-once bound there is immediate depolarisation
-electrical differences due to K+ and Na+
-ionotropic
what are NMDA receptors
-NMDA receptors often co-exist with AMPA receptors
-NMDA receptors have a voltage-dependent Mg2+ block
-So, NMDA receptors only open when the neuron is already depolarised
-NMDA receptors let Ca2+ in ->leads to downstream signaling
-NMDA receptors function as a coincidence detector: when a neuron is activated right after it was already activated
-ionotropic
how does glutamate interact with metabotropic glutamate receptors
-receptor: G-protein coupled receptor
-example rec: mGluR1, mGluR2
-mechanism:Activate G-protein, trigger downstream signalling cascade
-speed: slow (sec-min)
-mGluRs allow glutamate to sometimes be inhibitory (e.g., in the retina)
whats GABA
-γ-amino butyric acid
-Not an amino acid used to synthesise proteins
-Synthesised from glutamate by the enzyme glutamic acid decarboxylase
-Action is terminated by selective uptake into presynaptic terminals and glia
why is GABA normally an inhibitory neurotransmitter
-Most common inhibitory transmitter in the CNS
-Produces IPSPs (inhibitory postsynaptic potentials) via GABA-gated chloride channels (GABAA receptors), if the membrane potential is above chloride’s Nernst potential
-The right amount of inhibition via GABA is critical:
=Too much -> coma or loss of consciousness
=Too little ->seizures
-the membrane potential is described by the Goldman equation, which shows that the membrane potential is influenced more by the ions for which the membrane is more permeable
how does Modulation of GABAA receptors work
-Other chemicals can bind to the GABAA receptor and modulate the response to GABA binding
-These chemicals have no effects without GABA binding (allosteric drug)
-Ethanol (alcohol)
Benzodiazepines e.g. diazepam, used to treat anxiety
-Barbiturates are sedatives and anti-convulsants (seizures)
-Neurosteroids are metabolites of steroid hormones e.g. progesterone
-alcoholics have increased inhibitions which leads to a decrease in receptors therefore alcoholics have seizures when they stop because there is a decrease in recs therefore decreased inhibition
how does GABA act via metabotropic GABAB receptors
-Like the mGluRs, GABAB receptors are GPCRs
-They act in diverse ways in different cells, but might:
=open K+ channels (hyperpolarisation)
=close Ca2+ channels
=trigger other second messengers like cAMP
-Often presynaptic or autoinhibitory
whats glycine
-Inhibits neurons via glycine-gated chloride channel (glycine receptor)
-But it also binds to NMDA glutamate receptors
whats spatial summation
-lots of signals at the same time are adding up together
why does it matter if excitatory and inhibitory synapses are arranged spatially
-An inhibitory synapse can block the propagation of an EPSP toward the soma
-GABAA receptors don’t always produce an IPSP, e.g. if Vm is near chloride’s Nernst potential
-In this case, they act by shunting inhibition
-Opening chloride conductance decreases the membrane resistance ->current leaks out the membrane
