Neurotransmitters Flashcards
Major Neurotransmitters
Glutamate: Amino Acid*
Norepinephrine: Catecholamine
Neurotensins: Neuropeptide
2-Arachidonoylglycerol: Neuroactive lipid*
Glutamate - General Role
Primary excitatory NT in brain Ubiquitous distribution Asymmetrical synapses Outflow neurons Does not cross blood brain barrier
Glutamate - Synthesis (Minor)
alpha-Ketoglutarate from Krebs cycle
Glutamate dehydrogenase (Aminotransferase)
NADPH
Glutamate - Synthesis (Major)
Glutamine precursor
Glutaminase family of enzymes
In neuron mitochondria
Glutamate is converted back to glutamine via glutamine synthase in astrocytes
Glutamate - Storage
Synaptic vesicles
Accumulated into vesicles via specific transporters (VGluT)
Glutamate - Release
Triggered by increase in intraceullular calcium
Presynaptic receptors for glutamate that inhibit release
Act by reducing the sensitivity of the release process to calcium
Activated by glutamate itself; therefore it is a negative feedback process
Glutamate- Inactivation
Primary mechanism is cellular uptake of released glutamate
Accomplished via glutamate transporters (EATT) present on the plasma membrane (being charged, glutamate will not go through membranes on its own)
Glutamate plasma membrane
Different from VGluTs
Excitatory Amino Acid Transporters (EATTs)
High expression in astrocytes, lower in neurons
Secondary active transport, Na is driving
Gliutamate-glutamine shuttle
Glutamate is released vesicularly by neurons
Glutamate is taken up by astrocytes (EATT)
Glutamate converted to glutamine is astrocytes
Glutamine is released by astrocytes and taken up by neurons (EATT)
Glutamine is converted back to glutamate and packed into vesicles
Glutamate - Reason for complexity
Glutamate extracellular is toxic to neurons
Astrocytes are plentiful, surrounding synapse
Glutamine extracecllular is safer
Glutamate - Ionotropic receptors
AMPA (Na/K)
Kainate (Na/K)
NMDA (Na/K/Ca)
NMDA Receptor Mechanism
High conductance channel Conducts calcium in addition to sodium Requires glycine co-factor Slow kinetics At resting potential has Mg blocker Depolarization drives Mg out
NMDA Role
Influx of calcium results in activativation of kinases: Memory formation and plasticity
Too much calcium is toxic so difficult to activate NMDA
Glutamate - Metabotropic receptors (mGluR)
GPCRs
Glutamate - Physiology
Glutamate receptors found primarily on dendrites
AMPA receptors (conduct sodium) underlie the majority of excitatory, fast transmission in the brain
Exert excitatory effects; move the membrane potential toward threshold (produce excitatory slow potential)
Glutamate - Pathophysiology
Overactive glutamatergic systems
Occur when brain is deprived of oxygen/glucose
No energy to keep glutamate concentrations low; results in hyperexcitability (seizures)
Huntington’s disease and amyotrophic lateral sclerosis (ALS, Lou Gehrig’s disease)
2-AG - Brain distribution
Striatum Cerebellum Limbic cortex Hippocampus Amygdala Same targets as THC
2-AG - System efects
Motivation to engage in rewrding behaviors: eating, drug taking Mood setting Fear responses Stress responsivity Balance and posture Habit learning
2-AG - Synthesis
Made on demand; not vesicle stored
Two enzyme cascade with PIP2 precursor
PIP2 to DAG via PLC
DAG to 2-AG via DAG Lipase
2-AG - Synthesis Regulation
DAG Lipase
Found in neurons that are across the synapse from the receptor for 2-AG
Intracellular calcium
Activation of PLC and an increase in intracellular calcium
Growth factor receptors and GPCRs activate PLC
2-AG storage and release
No storage in any type of vesicle
Release is simultaneous with synthesis
Therefore, release is regulated by synthesis
Release process: diffusion through membranes
2-AG: Inactivation
Enzymatic via monoacylglycerol lipase (MGL)
Results in the formation of glycerol and arachidonic acid, neither of which bind the receptor for 2-AG
Unregulated; intracellular
2-AG Receptor
CB1 - Cannaboid receptor
GPCR
Almost always found on presynaptic nerve terminal
Inhibits opening of voltage operated calcium channel, NT release
2-AG Physiology and Pathophysiology
Fat, dumb and happy; calm, cool, collected
Overactive: Obesity?
Underactive: Depression
