Linger Pharm Neurotransmitters Flashcards
Sites of Drug Action in the CNS
(1) Action potential in presynaptic fiber;
(2) synthesis of transmitter;
(3) storage;
(4) metabolism;
(5) release;
(6) reuptake into the nerve ending or uptake into a glial cell;
(7) degradation;
(8) receptor for the transmitter;
(9) receptor-induced increase or decrease in ionic conductance;
(10) retrograde signaling.
Monoamine Transporters:
Commonly used drugs such as antidepressants, amphetamines, andcocainetarget monoamine (norepinephrine,dopamine, and serotonin) transporters with different potencies.
Normally, norepinephrine(NE) reuptake back into the noradrenergic neuron occurs via thenorepinephrinetransporter (NET), and subsequently a proportion is sequestered in presynaptic vesicles through the vesicular monoamine transporter (VMAT).
Meth and cocaine, e.g., affect these pathways
Monoamine Transporters: Therapeutic applications
ADHD: methylphenidate, amphetamine
Depression: SSRIs, SNRIs, TCAs
Enzymatic Termination of Response
Also enkephalins, endorphins, and other neuropeptides
Therapeutic Applications for AChE inhibitors:
Alzheimer’s disease
Myasthenia gravis
Glaucoma
Chemical warfare: sarin gas
Organophosphate pesticides
Major Classes of Neurotransmitters (NTs)
Amino Acid Transmitters (Glutamate, aspartate, GABA, Glycine)
Peptides (Opioids, Tachykinins)
Small Molecule Transmitters (Ach, Monoamines- catecholamines, serotonin; Histamine)
Endocannabinoids
Neurotransmitter (NT) Receptors
Each chemical signaling molecule has its own receptor(s)
Receptor binding is selective, but not specific
Almost all chemical signaling molecules have several * receptor subtypes:
- In some systems the potential number of receptor variants is enormous
- Consider a receptor composed of five subunits.
- – If there are four distinct subunits (a, b, g, d)
- – And there are five or more variants of each subunit (a1, a2, a3, a4, a5, b1, b2, …etc.)
- – Then how many possible combinations using five subunits are there?
Each receptor subtype is coupled to a specific signaling mechanism and/or has cell type-specific components in the signaling cascade
Neurotransmission at Chemical Synapses
Synaptic vesicle transport to nerve terminal
Neurotransmitter synthesis and packaging into vesicles
Depolarization of the presynaptic nerve terminal by an arriving action potential causes influx of Ca++ via opening of voltage-dependent Ca++ channels
Fusion of vesicles with plasma membrane and release of vesicle contents into synaptic cleft
Binding and activation of postsynaptic receptors
Postsynaptic membrane response
Elimination of transmitter from synapse by reuptake transporter or
Elimination of transmitter from synapse by enzymatic breakdown
Types of Ion Channels and NT Receptors
Voltage-gated channels respond to changes in membrane potential
- Axonal Na+ channels mediate the fast action potential
- Ca++ channels in the presynaptic terminal stimulate NT release
Ligand-gated ion channels (Ionotropic)
G protein-coupled receptors (Metabotropic)
Voltage-gated ion channels
Example: Na+ channels (Nav1.1 – Nav1.9)
Structure: 4 x 6 TM domains
Activated in response to membrane depolarization
Function: propagate action potentials
Ligand-gated ion channels
Example: nicotinic AChRs (nAChRs, neuronal and muscle subtypes)
Structure: pentamer of 5 subunits, each containing 4 TM domains
Activated in response to ligand binding
Function: excitatory neurotransmission, muscle contraction, etc.
Ionotropic
receptors
Multiple subunits; transmembrane domains form an ion channel
Ligand binding causes a conformational change resulting in opening or closing of the channel
Extracellular domain with binding site for NT (also agonist and antagonist binding sites)
Membrane spanning domain that forms the ion channel
Intracellular domains that may interact with other proteins
Mediate fast (msec) synaptic transmission
Metabotropic
Single subunit with seven membrane-spanning domains
Ligand binding stimulates a G protein-coupled signaling cascade and second messengers
Receptor: ligand binding protein
GTP binding protein (a, b, g subunits)
Effector protein (ion channel or enzyme)
Mediate slow (sec to min) synaptic transmission
Ionotropic vs metabotropic-
Excitatory or Inhibitory
Ionotropic:
- Excitatory Postsynaptic Potential (EPSP): Influx of Na+ or Ca++ causes membrane depolarization
- Inhibitory Postsynaptic Potential (IPSP): Efflux of K+ or influx of Cl- causes hyperpolarization
Metabotropic
- Excitatory and inhibitory G protein pathways
Ionotropic
NT Ligands
Glutamate
GABA
Acetylcholine
Serotonin
Glycine
Metabotropic
NT Ligands
Glutamate GABA Acetylcholine Dopamine Norepinephrine Serotonin Histamine Neuropeptides Endocannabinoids
A 75 yo man with atrial fibrillation experiences a stroke when an embolus lodges in the proximal portion of his left middle cerebral artery. He immediately loses his ability to talk and experiences paralysis of his right arm and leg. A small portion of his left cortical hemisphere has substantially reduced blood flow for several hours and is irreversibly damaged. Excess of which neurotransmitter contributes most to the cell death of neurons in this case?
Acetylcholine Dopamine GABA Glutamate Serotonin
Glutamate
Glutamate Excitotoxicity
Calcium may trigger apoptosis and a host of degradative intracellular enzymatic processes
This “excitotoxicity” leads to irreversible damage to neurons
Glutamate: The Primary Excitatory NT
Localized throughout the CNS
Glutamate accounts for most fast synaptic transmission in the CNS and spinal cord
Synthesized locally from glucose or from glutamine transported into neurons from surrounding glia
Glial cells surrounding glutamatergic neurons are essential for Glu reuptake and termination of signal
A 73 y/o well-educated woman is brought to the physician by her daughter, who has become concerned about her mother’s behavior. The mother volunteers at the local library shelving books, but for the past few months she has had trouble remembering where the books go. In addition, she often forgets to turn the stove off after cooking her family’s long-time favorite dishes. A drug with which of the following mechanisms of action is most likely to reduce deterioration?
AMPA receptor agonist AMPA receptor antagonist NMDA receptor agonist NMDA receptor antagonist mGluR receptor agonist
NMDA receptor antagonist – memantine
Glutamatergic Receptors: Ionotropic
N-methyl-D-aspartic acid (NMDA)
- Na+/K+/Ca++ channels
- Needs co-agonist glycine
- Channel blocked by Mg++ until depolarized
- Important in ischemia, hypoxia – cell death
- Subtypes: NR1, NR2A-D
Non-NMDA (AMPA/Kainate)
- AMPA receptors mediate the vast majority of excitatory synaptic transmission in the brain
- Na+/K+ channels; some are permeable to Ca++
- Subtypes: GluR1, GluR2, GluR3, GluR4
Glutamatergic Receptors: Metabotropic
Postsynaptic receptors decrease K+ conductance and increase IP3 and DAG
Presynaptic mGluRs act as autoreceptors to inhibit Glu release
- Decrease Ca++ conductance; decrease cAMP
The NMDAR: A Coincidence Detector
A single synaptic input results in the generation of a short-lasting excitatory postsynaptic potential (EPSP) that is mediated entirely by AMPA receptors.
When multiple inputs occur simultaneously, nerve depolarization removes the Mg++ block in NMDA receptor channels and the same single synaptic input generates a longer-lasting EPSP that is mediated by both AMPA and NMDA receptors. Thus, the NMDA receptor can “sense” the activity in adjacent inputs.
