← 3/10/09
← GluRs – Metabotropic glutamate receptors: mGluRs
← L-glutamine
↓ (via glutaminase)
← L-glutamate (mitochondrial)
←
← α-ketoglutarate (mitochondrial)
←
← dicarboxylate carrier outside of mitochondria
α-ketoglutarate (cytoplasmic)
L-glutamate via AA (cytoplasmic)
GS or GAD (in glia)
L-glutamine GABA (inhibitory neurons)
← Na+- dependent:
Excitatory Amino Acid Carrier-1 (EAAC-1)
Glu Transporter-1 (GLT-1)
Glu Aspartate Transporter (GLAST)
← H+ and Mg2+ dependent:
Vesicular ATP-ase Glutamate Transporter (VGlu-T)
← Na+ and H+ dependent:
Glutamine Transporter (Gln-T)
←
← Current structural model of mGluRs – Homodimers
Regional expression varies: mGluR1, 5, 6 – due to experience!!
Class I
o mGluR1 and mGluR5
o IP3 and Ca2+
Class II
o mGluR2 and mGluR3
o cAMP
Class III
o mGluR4 and mGluR6-8
o cAMP
←
← mGluR Functional Attributes
Involved in:
o perception of pain
o mood/affect, especially anxiety
o learning and/or memory
o blood flow / headache
Modulation of the activity of:
o Voltage-dependent ion channels
o Transmitter release
o Ca2+-dependent ion channels (K+)
o Ligand-gated ion channels
←
← Group I Effecter Mechanisms
← Glu
←
← mGluR1/mGluR5
←
← Gq
←
← PLC & PIP2
←
← IP3 + DAG
←
Ip3R PKC
AGO (competitive)
Glu endogenous
Ibotenate
DHPG (3,5-dihydroxyphenylglycine)
← ANT (competitive)
CPG (carboxyphenylglycine; especially 4-CPG)
← Group I agonist can increase excitability
There is no AHP after DHPG is added; spike-frequency accommodation blocked
and easily excited
But both pre and postsynaptic effects are observed
cause headaches & reduce transmitter release by reducing Ca2+ influx
← Group II, III Effector mechanism
← Glu
←
Group II, III
←
Gi
←
AC
cAMP
← PKA
← Group II
AGO
o Glu
o NAAG (N-acetylaspartylglutamate)
ANT
o EthGlu (ethylGlu)
← Group III
AGO
o Glu
o AP4
ANT
o MAP4
←
←
←
←
←
←
←
←
←
←
←
← GABABRs II
← GABA biosynthesis and metabolism
← Glu
← (GAD)
← GABA
← (GABA-T) *blocked by GABAculine
← Succinate Semialdehyde
← (SSDH) *blocked by Valproate
← Succinate
←
← Valproate strongly facilitates CNS inhibition
It facilitates the GAD enzyme and prevents the breakdown of GABA. This
increases the transfer from Glu GABA. This causes inhibition!
←
← GABA Transporters (GAT) Pharmacology
VGAT (vesicular GABA transporter): GABA
o Nipecotate
o Vigabatrin
GAT1 (neuronal, glial): GABA
o Nipecotate
GAT2 (pia, arachnoid): GABA, Beta-alanine
o Nipecotate
GAT3 (neuronal, glial): GABA, Beta-alanine
o Nipecotate
←
← GABAergic synapse
Package GABA into vesicles and release it onto GABARs that generate IPSPs.
Presynaptically there was an action potential. GABABR are found posynaptically
and presynaptically. There are differences in their interaction tho. The GABA can
be transported back presynaptically and it can be transported into mitochondria
or broken down they can also be broken down in glial cells.
←
←
←
←
←
← Two Subunits: Co-expression
GABA B receptors are obligate hetero-dimers: one GABA b1 and one
GABAb2 subunits are needed. One binds the g-protein and one binds to
the GABA.
GABA b1 and GABA b2 subunits exist and co-expressed in the same cells and
regions and rate.
If you only express GABA b1 then they are stuck in the endoplasmic membrane
and doesn’t make it to the plasma membrane. If only gabab2 are expressed
then the GABA doesn’t interact with the receptor.
←
← GABABR-Effector coupling
GABA binds to one of the two components of the dimmer and activating the g-
protein on the other part of the dimmer.
The Gi/o family of proteins;
o The α subunit ↓ the AC
o The βγ subunit ↓ VDCCs (blocking depolarization) and ↑ the activity of
VDKC (decreases the resting potential).
PTX (pertussis toxin blocks the Gi/o Proteins).
←
← GABABR ligands
AGO
o GABA (endogenous)
o Baclofen (exogenous antispasmatic drug)
ANT
o Phaclofen
o 2-OHsaclofen
←
← Effects of divalent cations on GABABR ligands binding
Some enhance GABA binding
o Mn2+ = NI2+ >Mg2+ >Ca2+
o Physiological [Mg2+] or [Ca2+
Some inhibit GABA binding
o Hg2+ > Pb2+
AChE ligands I: Organophosphates – the ACh is left inside the synapse and the AChE
isn’t able to do its job.
Ligand Duration Use (dose dependant)
Long Irreversible Insecticide WMD
Sarin [GB] X X
DDT X X
Diazinon X X
Malathion X X
5 Classes of mAChRs
Name M1 M2 M3 M4 M5
Effectors Gq Gi Gq Gi Gq
Evens Odds
- ↓ AC - ↑ PLC
- Modulate IM
Uses/abuses of mAChR ligands
- Clinical
o reduce secretions (atropine)
o prevent motion sickness (scopolamine)
o treat Alzheimer’s (Donepezil)
o treat autonomic disorders (M3 ANT)
o dilate pupils for ophthalmic exams (M3 ANT)
o treat severe diarrhea (M3 ANT)
o slow heart rate (M2 AGO)
o treat mushroom/anti-AChE poisoning (atropine)
- Non-clinical
o dilate pupils for beauty (atropine)
mAChR Agonists
LIGAND Receptors
M1 M2 M3 M4 M5
Acetylcholine X X X X X
(ACh)
Carbachol X X X X X
Muscarine X X X X X
Oxotremorine X X X X X
Pilocarpin E X
mAChR Antagonists
LIGAND Receptors
M1 M2 M3 M4 M5
Atropine E X X X X X
Scopolamine X X X X X
Pirenzepine X
Gallamine X
4-DAMP X
Tropicamide X
Smooth muscle contraction via M3 mAChRs via IP3R mediated Ca2+ nM muscarine
Catecholamine biosynthesis
Tyr (tyrosine crosses BBB)
TH (tyrosine hydroxylase)
DOPA
AAAKC or DDC
Dopamine (in the VTA and SN this is the end)
DA Beta hydroxylase
Norepinephrine (adonergic)
PNMT
epinephrine (in adrenal cortex)
TH: The rate limiting enzyme
- it has several amino acids that can be phosphorylated. Cam-KII, PKA, PKC, ERK, and cdc-
like-K. PHosphorylating increases activity and phosphotases decrease activity.
DA degradation
DA
COMT MAO + aldehyde deOH
3-methoxy-tyramine DOPAC
MAO COMT
HVA
Reuptake inhibitors
DAT NET SERT
(DA transports) (NE transporter) (5-HT transporter
Indatraline*
cocaine
Bupropion (wellbutrin)*
Nomifensine (merital) Reboxetine* Fluoxetine* (frozac)
Duloxetine (cymbalta) Atomoxetine** Sertraline* (Zoloft)
Amphetamine Imipramine* Citalopram* (Celeza)
Amitriptyline* Paroxetine*** (Paxil)
Fluvoxamine*** (Luvox)
Venlafaxine*
Clomipramine***
*antidepressants
** ADHD
*** anxiolytics/antiOCD
DA-specific neurotoxins
MPTP glial MAO-B MPP+ (shuts down kreb cycle in mitochondria)
6-OH-DA
1. Both MPP and 6OH DA are substrates for DAT
2. Both are then taken into mitochondria
3. Both block oxidative metabolism
4. Both kill DA neurons selectively and dose-dependently
5. Both produce behavioral effects mimicking Parkinsonism
DAR types
Name D1 D2 D3 D4 D5
Synaptic Post- Pre- and Post- Post- Post-
location Post-
Alpha Gs Gi Gs
subunit
effector
Beta Decrease
gamma VDCC, VDKC,
subunits CDKC
effects
The ctx has D1-D5
Hypothalamus has D3 + D5
Corpus striatum has D1 + D2
DA agonists
Ligand Other catecholamine
DA receptor type
receptors
D1 D2 D3 D4 D5 Alpha beta
Dopamine X X X X X X
Apomorphine X X X X X
Dihydrexidine XX X
Bromocriptine X X X
Praminpexole X XX
Ropinirole X XX
DAR antagonists
Ligand DA receptor type
D1 D2 D3 D4 D5
Spiperone XXX XXX XX XX XX
Ecopipam X
Amisulpride XXX X
Chlorpromazine* XX X X
Trifluoperazine* XX X X
Haloperidol* XX X X
Resperidone* XX X X
*out-patient drugs
Tardive dyskinesia – intermittent inability to move. The receptors increases and then
they can’t create more. They are taken off neuroleptic drugs they return to the drugs after
symptoms of origional problem comes back.
Norepinephrine (NE)
Uses/abuses of NE ligands
- Clinical
o Cardiac regulation (rhythm, rate, volume)
o Antihypertensive
o Bronchial dilation (asthma relief)
o Anti-depressant
o Anti-ADHD/ADD
o Anti-OCD
o Decongestant
- Recreational
o Hallucinogenic
o Amphetamine-like effects
Alpha 1 (α 1) Adrenoceptors
Name α 1D
α 1A α 1B
Expressed in: CNS, heart, liver, Resistance vessels, CNS, aorta, lung,
(don’t need to know) urogential smooth kidney, spleen bladder
muscle
Non-selective AGO DA
NE
EPI
Phenylephrine (nyquil)
Ephedrine, Pseudoephedrine
Selective AGO Tetrahydrozoline
(eyedrops)
Serotonin (5-HT)
Peripheral 5HT
- first purified from blood plasma (serotonin): 1948 and first purified from the brain in
1957
- total quantity of the body < 10 mg (5% of that in brain)
- Intestines 0 enterochromaffin cells enhance motility of 5HT4
- Blood vessels – platelets; vasoconstriction: 5HT1D
- Also a mitogen: enhances cell proliferation in muscle, liver but not in the bone
5HT pathways: Raphe n. which are widely distributed from the pons down the brainstem
and project throughout the rest of the brain. The largest are the dorsal and median Raphe
n. They are pyramidal neurons and they have afterhyperpolarization (modulated by
apamine). These neurons are important in the sleep/wake cycle. They are almost
completely silent when sleeping and active during waking.
5HT1Rs
5-HT1A 5-HT1B 5-HT1D 5-HT1e 5-
HT1f
Tissue Neuronal; smooth Rodent neuronal Human Widely distributed
muscle autoreceptor; neuronal
smooth muscle autoreceptor;
constriction smooth
muscle
constriction
Ubiquitous 5-HT
agonist Quipazine
Selective Buspirone Ergotamine (mold)
full agonists DMT Sumatriptan
(dimetheyltryptamine)
Selective Spiperone Isamoltane
antagonists
Antagonist Pindolol
G-Protein G i/o
Anziolytic (5HT1a agonist) – Buspirone
5-HT2Rs
5-HT2A 5-HT2B 5-HT2C
Nonselective 5HT
AGO Quipazine
Partial AGO LSD-25 LSD-25
Psilocybin/psilocin Psilocybin/psilocin
Pyschedelic Pyschedelic
phenylethylamines phenylethylamines
Selective DMT agomelatine
AGO DOM (STP)
Selective ANT Ketanserin Metergoline ritanserin
Nonselective Mesulergine
ANT dibenzyline
G-Protein Gq
5HT3Rs
5HT3Rs
Nonselective AGO 5HT
Quipazine
Selective AGO CBG
Selective ANT Ondansetron (keeps you from vomiting)
Zacopride
Mechansism Petameric cation channel (weak selectivity
for Na+)
Antiemetics (5HT3 antagonists) – used extensively to alleviate nausea in chemotherapy
- Ondansetron
- Zacopride
- also used in IBS treatment
Nootropics (5HT3 antagonists) – the problems is they don’t cross the BBB and would cost
$100/dose/day to take enough drugs to cause the nootropic effects.
5HT4-like receptors
5HT4 5HT6 5HT7
Nonselective 5HT
agonists Quipazine
Selective AGO EMDT COAT
Selective ANT Amoxipine
Nonselective ANT Clozapine
G-protein Gs
5HT5Rs
5-ht5a 5ht5b
Nonselective AGO 5HT
LSD
5HT specific neurotoxin
- PCPA: highly specific for 5HT neurons similar in mechanism to MPP+
Melatonin - just know that it is serotonin synthesizes melatonin in pineal
←
← Histamine
← Peripheral HA
← - Inflamation (in mast cells): H1Rs
orgasm
allergy
congestion
← - Digestion: H2Rs
gastrin
Parietal cells create gastric acid
← - Immune Response: H4Rs
basophils
neutrophils
bone marrow
←
← HAminergic neurons: transport, synthesis, degradation
L-amino acid transporter takes HA into the cell (AAAT)
Histidine is converted by histidine decarboxylase (HD) into histamine and
transported into vesicles via Vesicular MonoAmine Transporter (VMAT).
Histamine methyltransferase (HAMT) breaks down histamine into
telemethylhistamine
←
← CNS HA: Hypothalamic tuberomamillary nuclei* (TMN) project to the
rest of the body.
← *(right above the mamilary bodies)
←
← Tuberomamillary neurons (TMN)
← - large soma, dendrites
- long thin poorly myelinated punctate axons (slow, large number of synapes
← - adjacent to VLH hypocretin (hypothalamus cretine neurons)
HAR Types
Receptor H1 H2 H3 H4
g-protein Gq Gs Gi Gi
Neuronal Postsynaptic Postsynaptic Presynaptic postsynaptic -
location
Global Waking state; Waking state; Autoreceptor; ? -
Function arousal; appetite arousal regulate
suppression learning and transmission;
memory inhibit -waking
arousal
Other Mast cells Parietal cells Basophils;
Tissues neurophils;
bone
marrow;
smooth
muscle
Peripheral Inflammation; Acid release allergies
Function congestion;
orgasm
H3 is the only autoreceptor.
- If you block the receptor you increase firing rate of the postsynaptic neuron.
- H3 presynaptic block of Voltage Dependent Ca Channels.
- An AGO will decrease the inward current through VDCCs.
- Autoreceptors act like this
-
Uses/potentials of HA ligands
- Peripheral
o Allergy treatments (peripheral H1 ANT)
o Anti-congestive (peripheral H1 ANT)
o Anti-inflammatory (peripheral H1 ANT)
o Antacids (peripheral H2 ANT) *not really antiacids but go the problem of the
acid.
- Central
o Anti-emetics/anti-vertigo (H1 ANT)
o Hibernation, sleep (H1 ANT)
o Stimulants (H3 ANT)
o Alzheimer’s therapies (H3 ANT)
o Nootropics (H3 ANT)
o ADD therapies (H3 ANT)
o Anti-obesity treatments (H3 ANT)
HA Agonists
Competitive Agonist HAR
H1 H2 H3 H4
Histamine (HA) X X X X
Dimaprit X
Proxyfan (partial) X
Imetit X X
Classic antihistamines: Competitive ANT
Competitive ANT HAR
H1 H2 H3 H4
Cetirizine* (zyrtec) X
Clorpheniramine* X
Dimenhydrinate** (Dramamine) X
Diphenhydramine* (Benadryl) X
Doxylamine*** (Unisom) X
Fexofenadine* (Allegra) X
Loratadine* (Claritin) X
Meclizine** (Antivert) X
Promethazine** (phenergan) X
*allergy meds
**anti vestibular
***Sleeping pills
H3 antagonists: nootropic and dietary benefits…. Every learning task the H3 has
shown to enhance.