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
tx of severe alzheimer’s disease?
- NMDA receptor antagonist.
Glutamate receptor-mediated excitotoxicity may contribute to the pathogenesis of Alzheimer’s Disease: the NMDA receptor antagonist memantine is used to treat moderate to severe dementia of the Alzheimer type
stroke?
High concentrations of extracellular glutamate whether due to prolonged seizures or stroke may lead to apoptosis (cell death) of neurons
cause of seizure?
Excessively rapid or sustained firing of a relatively small group of glutamatergic neurons in one region of the brain may rapidly lead to successive excitation of ever larger numbers of glutamatergic neurons until a major region of the brain is evoked into a paroxysmal discharge – a seizure
tx of seizure?
GABAA GABAergic
- this is inhibitory, and seizure is when someone’s brain is overactive
tx of anxiety attack?
GABA drug: Alprazolam (Xanax)
Benzodiazepines
facilitate GABA-mediated opening of GABAA receptors (Cl- channel)
Examples: Alprazolam (Xanax), Diazepam (Valium), Midazolam (Versed), Clonazepam (Klonopin)
USE- Indicated for the treatment of generalized anxiety disorder and panic disorders, often in conjunction with psychotherapy
(however SSRIs and SNRIs, are now considered first-line agents for these disorders)
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 (inhibits NT release)
tx of early alzheimers?
- inhibit AChE
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
alcohol?
= inhibitory, it enhances the effects of GABA
Nicotinic receptors?
ionotropic ACh receptor: Na/K+ channels
(a) Increases cation conductance (excitatory)
(b) Located at neuromuscular junction (NM), postganglionic neurons (NN), CNS (NN)
Agonist: nicotine
Antagonist: curare-like drugs (nondepolarizing neuromuscular blockers)
muscarinic receptors
metabotropic ACh receptor
- M1 subtype is excitatory; decreases K+ conductance; increases IP3 and DAG (Gq)
- M2 subtype is inhibitory; increases K+ conductance; decreases cAMP (Gi)
Located on cells innervated by postganglionic parasympathetic neurons, on sweat glands, and in CNS
- Agonist: muscarine, pilocarpine
- Antagonist: atropine,
what can cause drowsiness, sedation and memory loss?
when CNS ACh receptors blocked
ACh is important in wakefullness, motor control and memory
Blockade of which of the following receptor systems is indicated to treat schizophrenia?
Dopamine D2
schizophrenia = too much dopa activity …. this increased activity is at D2 receptors (too much activation at the inhibitory receptors)!!!
** Classical antipsychotics work (in part) by blocking dopamine D2 receptors
however, serotonin is a newer class of antisychotic drugs
parkinsons?
Striatal DA neurons degenerate in Parkinson’s disease
SN → striatum regulates voluntary movement
drug addiction?
DA involved in VTA “reward pathway”
Cocaine blocks DA uptake
Amphetamines increase DA release (Meth)
D1 like family receptors
(D1,D5) is stimulatory: increases cAMP
D2-like family receptors
(D2, D3, D4) is inhibitory
- Presynaptic receptors decrease Ca++ conductance
- Postsynaptic receptors increase K+ conductance and decreases cAMP
alpha1 receptor
NE receptor = metabotropic Gq
Activation of α1 receptors is excitatory: Formation of IP3 and DAG, increased intracellular Ca2+
(a) Decreases K+ conductance; Increases IP3 and DAG
(b) Agonist: phenylephrine
(c) Antagonists: phentolamine, prasozin
alpha2 recepor
NE receptor = metabotropic Gi
Activation of α2 receptors is inhibitory: inhibition of adenylyl cyclase –> decreased cAMP
(a) Postsynaptic: Increases K+ conductance; decrease cAMP
(b) Presynaptic: Decreases Ca++ conductance
(c) Agonist: clonidine
(d) Antagonist: yohimbine
B1 receptor
NE receptor = metabotropic Gs
excitatory: Stimulation of adenylyl cyclase, increased cAMP
(a) Decreases K+ conductance; increases cAMP
(b) Agonist: isoproterenol
(c) Antagonist: propranolol
B2 receptor
NE receptor = metabotropic Gs
excitatory : Stimulation of adenylyl cyclase, increased cAMP
(a) Increases cAMP
(b) Agonist: albuterol
(c) Antagonist: butoxamine
tx of depression?
Fluoxetine (Prozac) - SERT Blocker – SSRI
depression is associated with decreased 5-HT function and is treated with SSRIs
ecstasy and LSD?
Ectasy (MDMA), LSD and other hallucinogens probably act in part by interacting with 5-HT receptors
5-HT3 receptor
only ionotropic seratonin receptor
Non-selective cation channel (Excitatory)
5-HT1 receptor
metabotropic seratonin receptor
inhibitory
5-HT2a
metabotropic seratonin receptor
5-HT2A is excitatory
5-HT4
metabotropic seratonin receptor
5-HT4 is excitatory
In terms of biosynthesis, what is one major difference between peptide neurotransmitters and small molecule transmitters?
neuropeptides:
- synthesized in cell body
- stored in large dense core vesicles
- can be co-localized w/ conventional NT’s
small molecule conventional NT’s:
- transmitters are made in the presynaptic terminals
- stored in small synaptic vesicles
- each one is located in a specific neuron
endogenous opioid peptides
Endorphins, Enkephalins, and Dynorphins
Morphine-like compounds involved in pain pathway
Potent pain relievers, such as morphine, oxycodone, and fentanyl, bind to opioid receptors
Receptors for the opioid peptides are present in the brain and peripheral tissues
Receptor subtypes and peptide selectivity: µ (endorphins), δ (enkephalins), and κ (dynorphins)
