Neuro (pt 1/4) Basic Overview, Neurotransmitters Flashcards
Nearly all drugs with CNS effects act on specific receptors that _______ ___________ _________.
modulate synaptic transmission
Respond to changes in the membrane potential of the cell.
-Mainly located on the initial segment and axon of the nerve and responsible for the fast action potentials which transmit the signal from cell body to nerve terminal
Voltage-Gated Channel
Consist of subunits and binding of a ligand directly opens the channel. Fastest response.
-Insensitive or weakly sensitive to membrane potential
-Respond to neurotransmitters
-Ex: GABA channel and Chloride
Ligand-Gated (Ionotropic Receptors)
Which is faster, metabotropic or ionotropic receptors?
Ionotropic Receptors are faster.
7 membrane G-protein coupled receptors, which, when bound, activates a heterotrimeric G protein.
Metabotropic Receptors
What are the 2 ways Metabotropic Receptors can regulate ion channels?
1) The activated G protein can interact directly to modulate an ion channel (all the action within the neuronal cell membrane)
2) The G protein can activate an enzyme that generates a diffusible second messenger (cAMP), which can interact with the ion channel or can activate a kinase that phosphorylates and modulates a voltage-gated channel.
Activation of presynaptic metabotropic receptors inhibit ______ channel function
calcium
Activation of post-synaptic metabotropic receptors activate _______ channels
potassium
Explain the physiology behind Electrical Synapses
1) Gap Junctions between pre and post-synaptic membranes permit current to flow passively through intercellular channels.
-Coupling through pore channels that matches up precisely with the postsynaptic pore channels, allowing ions to flow through
2) This current flow changes the postsynaptic membrane potential (change in charge)
3) This allows for initiation (or sometimes inhibition) of the generation of postsynaptic action potentials
-Depending on the ion flowing through, can be excitatory or inhibitory
Explain the physiology behind Chemical Synapses
1) There is no intercellular continuity and no direct flow of current from pre to post synaptic cell
2) Synaptic current flows across to the post synaptic membrane only in response to the secretion of NTs which open or close postsynaptic ion channels after binding to the receptor molecules
-Vesicle binds to presynaptic membrane, releasing the NT into the cleft
-NT binds to the receptor on the other side to continue the AP
The majority of CNS communication occurs through _____ synapses.
chemical
Resting membrane potential is typically ______.
-70mV
What are the Presynaptic Actions drugs can modify in chemical synaptic transmission to produce their effects?
-Drugs acting on the synthesis, storage, metabolism and release of neurotransmitters
-Block neurotransmission or neurotransmitter catabolism
What are the Post-synaptic Actions drugs can modify in chemical synaptic transmission to produce their effects?
Agonism or antagonism of the receptor
How can drugs effect Retrograde signaling to produce an effect?
The synapse can generate signals that feed back into the presynaptic terminal to modify neurotransmitter release (feedback loop)
A non-neuronal cell that has action in storage, homeostasis, support, protection, and provides structure to CNS tissues.
Glial Cell
All pathways directly involved in sensory perception (interpretation of environment) and motor control (how we move within environment)
Hierarchical Systems
Hierarchical Systems are composed of ?
Composed of largely myelinated fibers that can often conduct action potentials at a rate of more than 50m/s
What are the two types of neurons found in Hierarchical Systems?
1) Relay (Projection) Neurons
2) Local Circuit Neurons
-Transmit signals over long distances
-Relatively large cells
-Rare
-Excitatory neurons that stimulate Ionotropic receptors
-Release glutamate (excitatory NT)
Relay (projection) Neurons
-Smaller than Projection Neurons
-Myelinated
-Inhibitory neurons that release GABA or glycine
Local Circuit Neurons
Neuronal systems that contain one of the monoamines: NE, Dopamine, Serotonin, Acetylcholine
-Unmyelinated
-Slow
Nonspecific (Diffuse) Systems
What kind of receptors do the Nonspecific (Diffuse) Systems act on?
Metabotropic Receptors (GPCRs)
Describe the cell bodies, axons, and effects of the Nonspecific (Diffuse) Systems.
-Act on Metabotropic receptors (GPCRs)
-Cell bodies are in compact cell groups called the Locus Caeruleus (caudal pontine central gray matter)
-Axons are unmyelinated, conduct impulses slowly
-Long-lasting synaptic effects (can influence large areas of cortex by acting monosynaptically)
-Affect vast areas in a uniform way
-Implicated in sleep/waking, attention, appetite, and emotional state
What are the 3 Amino Acid Central Neurotransmitters?
-Glutamate (+)
-GABA (-)
-Glycine (-)
What are the 3 Monoamine Central Neurotransmitters?
-Dopamine (-)
-Norepinephrine (+)
-5-Hydroxytryptamine (5-HT: Serotonin) (-)
Describes the physiology of a Glutamate Synapse.
1) Glutamine is converted into Glutamate by glutaminase.
2) Glutamate is then concentrated into vesicles by the vesicular glutamate transporter (VGLUT).
3) Glutamate is released into the synaptic cleft via Ca dependent exocytosis (Voltage-Gated Ca Channel)
4) Glutamate activates post-synaptic Glutamate receptors (AMPA and NMDA ionotropic receptors or with metabotropic receptors mGluR)
5) Glutamate is cleared by Glutamate Transporters by the surrounding glia
6) Glutamate is converted to Glutamine by Glutamine Synthetase in the Glia (Stored)
-Mediates excitatory synaptic transmission
-Plays an important role in transmitting pain stimuli
Glutamate
What are the Ionotropic receptor subtypes activated by Glutamate?
AMPA: α-amino-3-hydroxy-5-methylisoxazole-4-propionicacid
-Present on all neurons
-Has to be activated before NMDA will work.
KA: kainicacid
-High levels in the hippocampus, cerebellum, and spinal cord
NMDA: N-methyl-D-aspartate
-Present on all neurons
-Requires glutamate binding + glycine binding at a separate site
What are the Metabotropic receptor subtypes activated by Glutamate? (all G-protein coupled receptors that act indirectly on ion channels)
I: Located post-synaptically
-Cause neuronal excitation by activating non-selective cation channels
-Activate Phospholipase C leading to IP3 mediated intracellular Ca2+ release
II & III: located presynaptically and act as inhibitory autoreceptors
-Inhibition of Ca2+ channels resulting in inhibition of neurotransmitter release
-Activation of these receptors causes the inhibition of adenylyl cyclase which decreases cAMP generation
-Ionotropic Receptor
-Present on all neurons
-Has to be activated before NMDA will work.
AMPA: α-amino-3-hydroxy-5-methylisoxazole-4-propionicacid
-Ionotropic Receptor
-Present on all neurons
-Requires glutamate binding + glycine binding at a separate site
NMDA: N-methyl-D-aspartate
-Metabotropic receptor activated by Glutamate
-Located post-synaptically
-Cause neuronal excitation by activating non-selective cation channels
-Gq
-Activate Phospholipase C leading to IP3 mediated intracellular Ca2+ release
I
-Metabotropic receptors activated by Glutamate
-located presynaptically and act as inhibitory autoreceptors
-Inhibition of Ca2+ channels resulting in inhibition of neurotransmitter release
-Gi
-Activation of these receptors causes the inhibition of adenylyl cyclase which decreases cAMP generation
II & III
Inhibitory neurotransmitter released from interneurons.
-Restricted to the spinal cord and brain stem.
-Receptors are selectively permeable to Cl-
Glycine
Inhibitory neurotransmitter released from interneurons.
-Present throughout the CNS
-Alpha & Beta
GABA
-The post-synaptic receptor
-Mediates the fast component of inhibitory action potentials
-Ionotropic receptors that are selectively permeable to Cl-
GABA Alpha Receptors
-Pre or post-synaptic receptor
-Mediates the slow component of inhibitory action potentials
-Inhibit adenylyl cyclase and cAMP generation
-Metabotropic receptors that either inhibit Ca channels or activate K+ channels.
GABA Beta Receptors
How do presynaptic, GABA Beta Receptors work?
Metabotropic receptors that inhibit transmitter release by inhibiting Calcium.
How do postsynaptic GABA Beta Receptors work?
Selective increase in K+ conductance, resulting in increased K+ efflux
-This hyperpolarizes membrane potential
-Makes it harder to fire an action potential
-Long lasting and slow (b/c the coupling of receptor activation to K+ channel opening is indirect and delayed)
What is the effect of Dopamine on CNS neurons?
Generally exerts a slow inhibitory action on CNS neurons
What are the two major pathways that Dopamine is located in?
1) Substantia nigra to the neostriatum
2) Ventral tegmental region to limbic structures esp the limbic cortex (Mesolimbic reward pathway - associated with addiction & substance abuse)
What are the 2 categories of Dopamine Receptors?
D1 Like: D1 and D5
D2 Like: D2, D3, and D4
All Dopamine Receptors are _______.
Metabotropic (GPCRs)
All noradrenergic receptors are ________.
Metabotropic
A neurotransmitter that enhances excitatory inputs by both indirect and direct mechanisms.
Norepinephrine
How does norepinephrine indirectly enhance excitatory inputs?
Disinhibition of local circuit neurons. (Inhibitory local circuit neurons are inhibited)
How does norepinephrine directly enhance excitatory inputs?
Blockade of K+ conductances that slow neuronal discharge.
-Mediates by Alpha 1 or Beta receptors
Where does Serotonin (5-Hydroxytryptamine) originate?
-Originates from neurons in the raphe or midline regions of the pons and upper brainstem
-Contained in unmyelinated fibers that diffuse most regions of the CNS.
What receptor subtypes does Serotonin act on?
All metabotropic receptors except for the 5-HT3 receptor (ionotropic)
What does the 5-HT3 receptor (ionotropic) do?
5-HT3 receptor (ionotropic) exerts a rapid excitatory action as a very limited number of sites in the CNS (ex: Zofran)
How does Serotonin (5-Hydroxytryptamine) cause its inhibitory effects?
Increases K+ conductance, causing membrane hyperpolarization.
-Strong inhibitory action
-Associated with regulatory functions of sleep, temperature, appetite, and neuroendocrine control.
5HT1A and GABAB receptors activate the same population of ______ channels.
K+
Often coexist in the same neuron with a conventional nonpeptide transmitter
Peptides
What are the examples of Peptides (Neurotransmitters)?
Often coexist in the same neuron with a conventional nonpeptide transmitter
Opioid peptides (enkephalins, endorphins)
Neurotensin
Substance P (involved in pain pathways)
Somatostatin
Cholecystokinin
Vasoactive intestinal polypeptide
Neuropeptide Y
Thyrotropin-releasing hormone
Involved in pain pathways.
-Contained in and released from small unmyelinated primary sensory neurons in the spinal cord and brainstem
-Cause a slow excitatory post-synaptic potential in target neurons
Substance P
How is Nitric Oxide generated?
-CNS contains a substantial amount of Nitric Oxide Synthase (NOS)
-NOS is activated by calcium-calmodulin and NMDA receptors which increases intracellular Ca2+, resulting in the generation of Nitric Oxide
-Not stored but synthesized on demand and immediately diffuses into neighboring cells
-Possibly responsible for long-term depression of synaptic transmission in the cerebellum
-Released from post-synaptic neurons and travel backwards across the synapse to the Cannabinoid Receptor (CB1) on presynaptic neurons and suppress transmitter release
-Affect memory, cognition, and pain perception
-Allosterics - enhancers of endogenous endorphins
Endocannabinoids
Which Neurotransmitters act on Ionotropic Receptors?
-Glutamate (+)
-GABA Alpha (-)
-Serotonin (+)
Which Neurotransmitters act on Metabotropic Receptors?
-Glutamate (+)
-GABA Beta (-)
-Acetylcholine M2 (-)
-Acetylcholine M1 (+)
-Dopamine (-)
-Norepinephrine (+)
-Serotonin (-)
