Neurotransmitters and Excitotoxicity Flashcards
Inhibitory post-synaptic potentials
Small, localized hyperpolarizations almost always associated with chloride entry into the cells. The move the cell further from threshold and make AP less likely
Excitatory post synaptic potentials
Small, localized depolarizations commonly produced by entrance of sodium and/or calcium into the cell.
Summations
Occurs in the post synaptic cell when multiple IPSPs and EPSPs are elicited by different synapses or by repetitive action of the same synapse (temporal or spatial summation). If there are more IPSPs than EPSPs, the cell is inhibited and no AP occurs and visa versa
Gs metabotropic receptors
Proteins activate adenylate cyclase which leads to increased production of cAMP from ATP. cAMP activates PKA which phosphorylates downstream targets, either increasing or decreasing activity.
Gq metabotropic receptors
Activate phospholipase C, which then creats IP3 (PIP) and DAG
IP3/PIP activates calcium release, or it can work with DAG to activate PKC which will phosphorylate downstream targets.
Fast transport
Usually associated with synaptic vesicles containing peptide neurotransmitters which cannot be made or recycled at the pre-synaptic terminal.
Slow transport
Used for structural or other components not needed quickly such as mitochondria and synaptobrevin. Also used for protein/chemicals needed at other locations of neurons such as voltage-gated sodium channels which are used at nodes of ranvier, not the pre-synaptic terminal. Fast route is direct route to pre synaptic terminal
Excitotoxicity
When something blocks the delivery of oxygen or glucose to the brain, the neurons in the brain will start to depolarize as the ATP levels fall. There is excess activation which allows huge amounts of calcium to enter the post-synaptic cell. This excess calcium leads to activation of enzymes that lead to the production of nitric oxide, damaging the membranes and even triggering apoptosis in the cortex
Catecholamines
Includes dopamine, epinephrine, norepinephrine
Synthesized from tyrosine by tyrosine hydroxylase
For epinephrine to be synthesized, its precursor norepinephrine must be released from the vesicle it was made in. Phenylethanolamine-N-methyl-transferase PNMT is then able to convert norepinephrine to epinephrine
4 major pathways using dopamine
Substantia niagra- important in controlling voluntary motion, related to Parkinson’s
Mesolimbic- this pathway runs from the ventral tegmental area to the nucleus accumbens. Related to pleasure/reward system
Mesocortical- runs from ventral tegmental area to the cortex, especially the frontal cortex. Crucial to attention and higher levels of consciousness. Damage is associated with alterations in cognition/consciousness. Dysfunction linked to schizophrenia
Tuberinfundibular- runs from hypothalamus to anterior pituitary. Suppresses prolactins release from pituitary
Catecholamine receptors
Alpha-1 uses Gq
Alpha-2 uses Gi
Betas use Gs
Dopamine binds its own receptors D1, D2 etc.. and activate Gi proteins
Location of serotonergic neurons in CNS
One cluster of neurons in the brain stem known as the midline raphe nuclei
Serotonin destruction
Like catecholamines, serotonin is also destroyed by monamine oxidase
Location of histaminergic neurons
Very specific nucleus of the posterior hypothalamus known as the tuberomammillary body
Histamine destruction
Diamine oxidase degrades histamine
Locations of Ach as neurotransmitter in PNS
NMJ Autonomic preganglionic synapses Parasympathetic post-ganglionic fibers Sympathetic post-ganglionic fibers for sweat glands/muscle vasodilators Amacrine cells in retina
Locations of Ach as neurotransmitter in CNS
Striatum (motor control)
Brainstem arousal system
-the circuit involving the peduculopontine tegmental and laterodorsal pontine nuclei
-also the basal forebrain arousal system (ventral output from reticular activating system)
-producing arousal (non-specific increase in cortical activity produced by sensory info arriving at brainstem arousal systems)
Synthesis of acetylcholine done by ___, then transferred into vesicle by
Caholine acetyltransferase
Vesicular acetycholine transporter protein VAchT
Ach destruction
True cholinesterase on post synaptic cell membrane
Pseudocholinesterase found in blood and acts on other choline esters
Broken into acetate and choline, choline is taken up by presynaptic cell for recycling
Atropine
Blocks muscarinic cholinergic receptors
M1-M5 location and effect
M1- post ganglionic neurons of ANS, broad distribution in CNS. Gq protein leads to increased IP3 and DAG
M2- cardiac- Gi protein decreases cAMP leading to increased K+ conductance
M3- smooth muscle of bronchi and vasculature- Gq leads to increased IP3 and DAG
M4- presynaptic autoreceptors controlling Ach release; striatum of basal ganglia for motor control- Gi leads to decreased adenylate cyclase
M5- cerebral vasculature and basal ganglia dopaminergic neurons for motor control- Gq protein leads to increased IP3 and DAG
Nicotinic receptor
5 subunits, each coded by different gene Alpha, beta, gamma, sigma, epsilon May be heteromeric or homomeric Fetal- 2 alpha, beta, gamma, sigma Adult- 2 slpha, beta, gamma, epsilon Change in subunit decreases the open time of the channel but increases sodium entry
Excitatory neurotransmitters in CNS
Glutamate, aspartate, maybe taurine
GABA- derivation, removal, metabolism of GABA
Major inhibitory neurotransmitter in brain
Found all over CNS
Derived from glutamate by glutamate decarboxylase (GAD)
Removed from synapse via GAT (GABA transporter)
GAT1- on presynaptic terminal (repackaged into vesicle as is)
GAT2- on glial cells like astrocytes (converted to glutamine then released to be taken back up by presynaptic cell and recycled back into GABA)
GABA, Stiff-person and diabetes mellitus diseases
Stiff-person: Increased muscle rigidity and muscle spasms associated with decreasing GABA content
Pancreatic beta cells produce and release GABA, so GAD is found in the pancreatic islet. Antibodies to GAD are most common identified type in Type I diabetes
GABA(a) receptor
Ionotropic
Related to nicotinic Ach receptor
5 subunits alpha, beta, gamma, delta, epsilon
Chloride chanel causing influx of chloride - IPSP
Benzodiazepine binding site on alpha subunit potentiates increase in chloride conductance
Also metabolites of progesterone and deoxycorticosterone potentiate its effects and produce drowsiness
GABA(b) receptor
Metabotropic-serpentine
Coupled to heterodimer G protein (two of them)
Decrease adenylyl cyclase, which leads to an increase in potassium influx and hyperpolarizes
Interacts with Gq system leading to DECREASE in IP3/DAG and decrease in calcium influx
Produce an IPSP
GABA(c) receptor
Found in retina
Pentamer of any of 3 different units
Ionotropic (also a chloride conductance)
Interstitial GABA
There is sufficient interstitial GABA to provide a continual background inhibition in the CNS
Mammalian has a lot of GABA receptors that are extrasynaptic and respond to interstitial GABA
It is believed that general anesthetics work primarily at these receptors
Glycine
Take home message- it does for the spinal cord what we think GABA does for the brain
Most prevalent inhibitory NT in the SC
Does exist in higher CNS but not as prevalent as GABA
Retina, Brainstem, Forebrain
Receptor is a pentamer- alpha subunit is site of binding
Ionotropic- chloride
Purines
Virtually every cell in body expresses some form of a purine receptor
PNS- sympathetic/parasympathetic nerves, sensory nerves, intrinsic nerves of gut/heart, motor nerves
CNS- Cortex, hippocampus, cerebellum, basal ganglia, midbrain, thalamus, brainstem
Strychnine
Blocks glycine receptor
Purine neurotransmitters
ATP- receptors largely post synaptic
Found in virtually all NT vesicles, so it is considered co-transmitter
Adenosine- many receptors are presynaptic (they regulate how much ATP is released). Some are clearly post-synaptic
Adenosine production, removal from synaptic cleft
ATP is released in ATPase breaks it down to ADP and then AMP
5-nucleosidase converts AMP into adenosine
Adenosine is sometimes considered second messenger since it was not the secreted neurotransmitter
Reuptake of adenosine, then adenosine deaminase in the cleft creates inosine, which is removed via circulation
Adenosine receptors
P1 receptors
Four subtypes A1, A2a, A2b, A3
Metabotropic, either increase or decrease cAMP production
ATP receptors
P2X receptros
P2X1-7
Ionotropic
Cationic ion channels- some allow sodium conductance, some allow calcium, others allow both
P2Y receptors
ATP or ADP can open
All have greater affinity for ADP
Eight different receptors
Metabotropic- most lead to Gq G11 activation, some lead to Gi and inhibition of adenylate cyclase
Adenosine functions
Sleep induction
Feedback inhibition of ATP release
ATP/ADP functions
Major role seems to be related to modifying the action of the “main” neurotransmitter that is in the same vesicle
Maintenance of long term potentiation (important for memory)
Modification of NT release- GABA, Norepinephrine, Ach, Glutamate and other excitatory AAs
Opioid locations
Striatum (basal ganglia) Hypothalamus Periaquaductal gray Nucleus parabrachialis (pontine) Raphe nuclei in brainstem
Opioid precursors
All have AA sequence Tyr-Gly-Gly-Phe-X Met-enkephalin Leu-enkephalin Octapeptide (X=Met-Arg-Gly-Leu) Heptapeptide (X=Met-Arg-Phe)
Pro-opiomelanocortinins (POMC)
Found primarily in pituitary and hypothalamus
Beta-endorphins
Other endorphins
Prodynorphins
Localized in hypothalamus, thalamus, brainstem, retina Gives rise to: 3 molecules of leu-enkephalin Dynorphin Alpha-neoendorphin Beta-neoendorphin
Nociceptin (orphaning FQ)
Has its own opioid receptor, does not bid to others
May participate in opioid induced Hyperalgesia
Opioid metabolism
All is enzymatic, likely after uptake
Enkephalinase A splits Gly-Phe bond
Enkephalinase B splits Gly-Gly bond
Aminopeptidase splits Tyr-Gly bond
Mu opioid receptor - binding causes what
Analgesia Respiratory depression Constipation Euphoria Sedation Increase GH and prolactin secretion Miosis
Kappa opioid receptor- binding causes what
Analgesia Diuresis Sedation Miosis Dysphoria
Deltoid opioid receptor- binding causes what
Analgesia
Commonalities b/w opioid receptors
All are serpentine receptors
Gi
Inhibit adenylyl cyclase
Indirectly alter other ion flows
Mu- increase K+ efflux and lead to hyperpolarization
Kappa/Delta- produce decrease in calcium influx
Endogenous endocannabinoid ligands
Anandamide (AEA)-degraded by fatty acid amide hydrolase (FAAH). Polymorphisms in this gene will cause reduced nociception, especially to heat
2-Arachidonylglycerol- degraded by mono-acyl glycerol lipase
Both can be metabolized via cyclooxygenase and ipoxygenase pathways *important- these pathways feed into prostaglandin synthesis
CB1 general info
Most abundant G protein receptor in the brain
Utilizes Gi- reduces adenylyl cyclase
Located on presynaptic terminals in CNS and PNS, mainly on EAA or GABA releasing neurons
Binds anandamide and 2AG equally well
Decreases NT release, effects are difficult to predict because it interacts with both EAA and GABA as well
Spinal cord CB1
Associated with modification of nociceptive inputs
Neocortical CB1
Associated with neuroprotection against excitotoxicity
Hippocampal CB1
Associated with changes in affect
CB2
Binds 2-AG better than anandamide
Located on microglia
Can be found on neurons in response to neuronal injury, brain inflammation responses
Modify cytokine release, can be anti-inflammatory
Found on GI tissue, linked to IBD treatment
Endocannabinoids are derived from
Membrane lipids- arachidonic acid
Occurs in presynaptic terminal
EAAs
Aspartate and Glutamate
NMDA receptor
Activated by EAAs
Ionotropic- allows calcium influx
NO is a byproduct of activating NMDA receptor
Glycine binding site- glycine must be present with EAA to activate channel
Magnesium binding site- Mg sits in channel and prevents Ca2+ influx when membrane is at resting potential (makes channel both voltage and ligand gated)
PCP binding site- PCP blocks the channel
Non-NMDA receptors
Ionotropic- primarily Na influx AMPA- Activated by EAAs AMPA has a Benzodiazepine binding site- reduces sodium influx when channel opens Kainate- Activated by EAAs -sodium and calcium influx
EPSP of EAA receptors
Activation of Non-NMDA receptors produces normal EPSP
NMDA receptor produces a long and slow EPSP because of the magnesium receptors blocking the channel at rest
Functions of Non-NMDA receptors
Primary sensory afferents
Upper motor neurons
Functions of NMDA receptors
Critical in short and long term memory formation
Synaptic plasticity in many forms
Getting rid of EAAs
EAAs are taken into glial cells after used and then converted glutamine and then released to be taken back up by pre-synaptic neuron to reform glutamate
NO effects on neurons
Long-term potentiation
In hippocampus & cerebellum
Cardiovascular and respiratory controls in pons/medulla
In high concentrations it is toxic to neurons and will kill the neighbors of the neuron that made it
Non-neural functions of NO
Relaxation of smooth muscle and vasodilation
