Pharm: NT's and Receptors Flashcards
ionotropic receptors
= ligand-gated ion channels: fast (10 msec)
NT binds causing a conformational change and directly opening or closing a channel causing a PSP–>
- sodium influx –> EPSP
- efflux of K+ –> IPSP
ex: nACHR
NTs: Glutamate, Gaba, Ach, Glycine**, Serotonin (note: Glycine is only one that is only ionotropic)
- have multiple subunits w/ a transmembrane domain that forms an ion channel: ligand binding causes conformational change resulting in opening/closing of channel
- may also have intracellular domain and cascade following influx of ion (i.e. Ca2+)
metabotropic receptors
= G protein coupled receptors: slower (20 sec)
indirectly modulate ion channels: NT binds activating a G protein –> signaling pathway
NT’s: Glutamate, Gaba, Ach, Dopa, NE, Serotonin, Histamine, neuropeptides, endocanabinoids
- single subunit w/ seven membrane spanning domains: ligand binding stimulates GPCR cascade and second messengers
- ligand binds to receptor, GTP binds to Galpha subunit and activates it and is hydrolyzed to GDP and becomes inactive
Glutamate
** primary excitatory NT!!!
- 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
Receptors:
- ionotropic receptors: Non-NMDA (AMPA), NMDA
- metabotropic receptors (Gq and Gi)
Pathophys:
- learning and memory
- excessive in seizure or strokes
- schizophrenia
GABA
gama-amino butyric acid = inhibitory
- localized throughout the CNS, principal NT of interneurons
Neurons located in striatum, globus pallidus, and Purkinje cells of cerebellum
Roles:
- Balances excitatory activity of glutamate
- GABA dysfunction leads to hyperexcited states
- GABA-mimetic drugs are used to induce sleep and control anxiety and seizures
Receptors:
- GABAa receptor = ionotropic:
- ligand gated Cl- channels hyperpolarize cell d/t influx of Cl- producing an IPSP - GABAb receptor = Metabotropic:
- Postsynaptic increases K+ conductance
- presynaptic decreases Ca++ conductance
ACh
synthesis ocurs in presyn. terminal from choline and acetyl-CoA by choline acetyltransferase
storage: Ach is loaded into vesicles by vesicle-associated transporter (VAT)
Receptors:
- ionotropic: Nicotinic (excitatory)
- metabotropic: muscarinic
- M1 = excitatory
- M2 = inhibitory
pathophysiology:
- NT in CNS as well in the peripheral autonomic nervous system and primary motor neurons (neuromuscular junction)
- CNS roles: midbrain reticular formation (level of wakefulness), basal ganglia (motor control), basal forebrain (connections to hippocampus and cortex involved in memory and motor skills), reciprocal relationship with dopamine in motor control
***Alzheimer’s Disease (AD): Patients with AD have reduced cerebral production of choline acetyl transferase, which leads to a decrease in ACh synthesis and impaired cortical cholinergic function; acetylcholinesterase (AChE) inhibitors are commonly used to treat AD; benefit is modest and may not impact long-term outcomes
**Neuromuscular junction diseases: myasthenia gravis, Eaton-Lambert Syndrome, botulism
**Drowsiness, sedation, memory loss - when CNS ACh receptors blocked
** A variety of drugs have the capacity to block muscarinic receptors in the CNS leading to “anticholinergic” side effects, particularly drowsiness
Dopamine
DA
- synthesis occurs in the presynaptic terminal from tyrosine by the enzyme tyrosine hydroxylase and dopa decarboxylase
- DA is loaded into vesicles by VMAT
receptors: metabotropic: D1-D5
- D1 increases cAMP, stimulatory
- D2 inhibitory
Pathophysiology:
- substantia nigra –> regulates voluntary mvmt (Striatal DA neurons degenerate in Parkinson’s disease)
- VTA “reward pathway” mediates: drug addiction and psychiatric disorders
NE
synthesis occurs inside NE granules from dopamine by enzyme dopamine beta hydroxylase
inactivation: reuptake into the presynaptic cell mediated by NE transporter (NET)
receptors (all metabotropic): a1, a2, B1, B2, B3
- a1: excitatory: Gq: decreases K+ conductance, increases IP3 and DAG
- a2: inhibitory: Gi; increases K+ conductance, decreased cAMP
- B1 and B2: excitatory; Gs: decreased K+ conductance, increased cAMP
pathophysiology:
- Modulates sleep, wakefulness, attention, and feeding behaviors
- Roles in learning and memory, anxiety and pain, and mood
seratonin
5-HT
- synth occurs in presynaptic terminal from tryptophan by enzyme tryptophan hydroxylase
- inactivation: serotonin uptake transporter - SERT (inhibited by many antidepressant drugs)
Receptors:
- Ionotropic: 5-HT3: non selective cation channel (excitatory)
- Metabotropic: 5-HT1 to 5-HT7:
- 5HT1 = inhibitory
- 5Ht2A = excitatory
- 5HT4 = excitatory
Pathophysiology:
- Mediates affective processes such as aggressive behavior and arousal
- Descending pain pathways
- Sensory enhancement
- Depression is associated with decreased 5-HT function: Treated with SSRIs
- Ectasy (MDMA), LSD and other hallucinogens probably act in part by interacting with 5-HT receptors
Histamine
all metabotropic
H1 receptor = excitatory: increased IP3 and DAG
H2 receptor = excitatory : increased cAMP
Amino acid transmitters?
excitatory: glutamate, aspartate
inhibitory: GABA, glycine
small molecule transmitters?
ACh, Dopa, NE, Seratonin, Histamine
excitatory vs. inhibitory ionotropic interactions?
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
xs of what NT contributes most to cell death in neurons during stroke?
Glutamate (excitatory)
- triggers Ca2+ influx in cells –> which may trigger apoptosis and host degredative intracellular enzyme process
- This “excitotoxicity” leads to irreversible damage to neurons
Non-NMDA receptor: GluR1, GluR2, GluR3, GluR4
ionotropic receptor for Glutamate
(AMPA, Kainate)
- AMPA receptors mediate the vast majority of excitatory synaptic transmission in the brain
- Ligand-gated Na+/K+ channels; some subunit configurations are permeable to Ca++
- Receptor subtypes: GluR1, GluR2, GluR3, GluR4
NMDA receptors: NR1, NR2A, NR2B, NR2C, NR2D
ionotropic receptor for Glutamate
Both ligand gated and voltage gated!
- Ligand-gated Na+/K+ channels highly permeable to Ca++
- Channels are also voltage-dependent; blocked by magnesium until depolarized and only allow entry of Ca++ if cell is depolarized (coincidence detector)
Receptor subtypes: NR1, NR2A, NR2B, NR2C, NR2D
*** Over-stimulation of these receptors is especially important in ischemia & hypoxia (stroke) where Ca++ influx via these receptors triggers cell death (apoptosis)
*** PCP, (phencyclidine = “angel dust”) and ketamine are noncompetitive antagonists at the NMDA receptor. At low doses these drugs cause hallucinations and delusions; at high dose they cause dissociative anesthesia.
where does PCP act?
*** PCP, (phencyclidine = “angel dust”) and ketamine are noncompetitive antagonists at the NMDA receptor. At low doses these drugs cause hallucinations and delusions; at high dose they cause dissociative anesthesia.
metabotropic glutamate receptors?
- Postsynaptic: Decreases K+ conductance; Increases IP3, DAG
- Presynaptic: Decreases Ca++ conductance (INHIBITORY); Decreases cAMP
NT involved in synaptic plasticity/learning and memory?
Glutamate! (NMDA receptor)
“coincidence detectors”
- a single synaptic input results in generation of EPSP thats mediated through AMPA (Non-NMDA receptors).
- When multiple inputs occur simultaneously nerve depolarization removes the Mg++ block in NMDA receptor channels and same single synaptic input generates a longer lasting EPSP - mediated by both AMPA and NMDA receptors… Thus the NMDA receptor can “sense” the activity in adjacent inputs
Migraine?
– excessive glutamate release contributes to the cortical spreading depression implicated in the aura of migraine headache
