The receptors have a long extracellular domain

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Transcript The receptors have a long extracellular domain

Inhibitory Neurotransmitters
• Most common in CNS are gaba (γaminobutyric acid) and glycine
• Made from serine
• Used in spinal cord neurons at about 50% of
inhibitory synapses
• The other 50% use gaba
• Rat poison that blocks inhibitory
neurotransmitter and cause excitation in
• Blocks glycine receptor that leads to
membrane depolarizations and over activity
and death due to seizures
• Most frequently used inhibitory NT in brain &
spinal cord. 1/3 of synapses use gaba
• Precursors are glucose, pyruvate and glutamine
• GAD= glutamic acid decarboxylase converts
glutamine to gaba
• Requires vitamin B6 derivative for GAD activity,
so B6 deficiency can cause gaba deficiency
• Noted when infant formula lacked B6=fatal
Re-Uptake Mechanisms
• Specific Transport proteins on presynaptic
membrane to reuptake intact NT
• Re-uptake into glial cell
• Diffusion
• Degradation by enzymes and re-uptake of
Gaba Removal
• High affinity gaba transporters
• Degradative enzymes are mitochondrial
Multiple Isoforms
• Each subunit can be encoded by any one of
several gene or mRNA products to make 3
subtypes of receptors A and C are
ionchannels, B is a metabotropic receptor
– GABA receptor
• 6 alpha subunit isoforms
• 3 beta subunit isoforms
• 2 gamma subunit isoforms
The GABA a and c receptor are members of the ligand-gated channel superfamily.
By analogy to the well studied nicotinic acytocholine receptors, GABAc receptors
are thought to exhibit the structure shown schematically in Fig. 2. These receptors
are pentomers, i.e. five subunits constitute the functional channel (Amin and
Weiss, 1996). The receptors have a long extracellular domain containing ligand
binding sites and several modulatory sites. In the middle of the receptor, GABA
gates an ionic channel. Binding of GABA to the receptor induces a conformational
change in receptor structure which leads to the opening of the channel.
From webvisionmed.utah
Neurotransmitter Receptors
100s NTs and 1000s or more NTRs
Receptors w/o NTs
Multiple Receptors for 1 NT
• How are they identified & classified
• How is this information used clinically?
Survey of NT Receptors
Figure 6-7:The neuropharmacology of cholinergic synaptic transmission
• From Latin means to bind (ligare)
• Any substance that binds a receptor or ion
– Neurotransmitters
– Plant & animal toxins
– Chemically synthesized compound
• Atropine, derived from belladona flower
– Antagonizes mAChR
– Ach effect on pupil of the eye is to constrict
– Form of atropine is used in dilatory eye drops
by opthamologists
Basic Structure of NT gated ion
• 100 nm long-barely extends the width of pm
• Subunits arranged to form a barrel with
interior pore through pm
• All subunits have common domains named
M1-M4 that are transmembrane
• M1-4 form hyophobic alpha helices
• Most are composed of 4-5 subunits
Drugs that bind GABAa
• Barbituate
– Phenobarbital = anesthetic
• Benzodiazapines = tranquilizers
– valium
• Binds GABAa subtype with gamma subunit
Effect of Drugs on GABA
• In the absence of GABA, drugs have no
• In the presence of GABA, drugs can
– Increase frequency of opening/benzodiazepines
– Increase duration of opening/barbituates
Pharmacology of VALIUM
• Valium=benzodiazapines bind to gaba gated
chloride channel
• Cause the channel to stay open longer==less
brain activity=calmer state of mind
• Used as anti-convulsant drugs
Fear and Anxiety and
Gaba A modulators
Anxiolytic drugsLibrium valium
Edvard Munch, the scream
By binding
Three types
Metabotropic vs ionotropic
Back to anxiety NT
Not the only
Hormonal brain
Metabotropic Ion Channels
Neurotransmitters bind Receptors that
are not ion channels
• Neurotransmitter binding and ion flux are
provided by two or more individual
• Allows for many effects of NT on postsynaptic cell
• Can regulate several channels, metabolic
enzymes and gene expression
• Stimulates or inhibits second messengers
Effect of Second Messenger
• May directly bind ion channel and regulates
its opening or closing
• Can activate enzyme s.a. cyclic AMP
dependent PKA that phosphorylates ion
channel to open or close it
Effect of Symp & Parasym on
Cardiac Muscle
• Parasympathetic presynaptic nerve ending
release Ach and slows heart rate
• Sympathetic presynaptic nerve ending
release NE and increase heart rate
Parasympathetic Cardiac
• Ach binds muscarinic Ach Receptor that
inhibits cardiac muscle excitation
• Ach binds receptor and the G protein alpha
subunit binds a potassium channel
• The K channel opens, hyperpolarizes the
cardiac membrane and leads to prolonged
relaxation phase of cardiac activity=slows
heart rate
Sympathetic Cardiac
• Ach binds B adrenergic Receptor that
strengthen cardiac muscle contractility
• NE binds B adrenergic receptor and the G
protein alpha subunit activates Adenyl
cyclase which produces cAMP
• cAMP activates PKA which phosphorylates
voltage gated calcium channel, prolonging
its opening time
• Effects mediated by second messengers
• Direct postsynaptic effects last several
hundred milliseconds to hours
• Secondary effects lasts days
• Postsynaptic electrical responses are weak
and slow
Second Messengers
• cAMP
• cGMP
DAG and IP3
Arachidonic acid
May act directly or indirectly on ion channel
How do G-proteins Work
• Can inhibit or activate downstream
molecules to increase or decrease levels of
second messengers
• Denoted Gs or Gi
G-proteins Link Channel Activity
with NT
• GTP-binding protein cycles between off
state (GDP bound) and on state (GTPbound)
• NT receptors catalyzes replacement of GDP
with GTP.
• Activated G-protein activates adenylyl
cyclase that produces cAMP
Short Cut Pathway
• NT binds receptor that is not an ion channel
but is linked to trimeric G protein
• G protein becomes activated by
conformational change transduced from
NTR that allows G to bind GTP
• Dissociates into a and bg subunit
• Gb subunit binds directly to ion channel &
gates it.
Long-Term Effects
• Ion channel can be regulated by G-protein directly
and by second messengers and enzymes s.a. PKA.
• So the effect of neurotransmitter binding can have
prolonged effects on ion channel activity.
• An activated NT receptor can bind to many G
proteins so signal is amplified
• 700 types of G proteins
G Protein Linked to Adenylyl
• Causes formation of cAMP and activation
of PKA
• PKA phosphorylates serine and threonine
residues on target proteins
Regulation of G protein
• Some NT bind to both Gi and Gs linked
• Allows for amplification of NT signal
• Allows for long term changes in post
synaptic membrane
G Proteins linked to
• Phospholipase cleaves PIP2 in the
• Generates to metabolic products each are
second messengers
• IP3 and DAG
• IP3 causes calcium release from
intracellular stores
• DAG activate PKC
Nitric Oxide (NO)
• Made from arginine by NO synthase
• Chemical exist gas form
• Released from post-synaptic terminal
without vesicles and acts on presynaptic
terminal = retrograde communication aka
retrograde messenger
• Lifetime is 5-10 min
NO relaxes Blood Vessels
• NO production is induced by ACh released
from parasympathetic nerve endings onto
endothelial cells in blood vessels
• mAchR activation leads to activation of NO
synthase & production of NO
• NO diffuses into underlying smooth muscle
NO Effect
• Binds iron co-factor in the active site of
guanylyl cyclase
– Enzyme that forms cGMP for GTP
• Leads to increase cGMP
• cGMP leads to smooth muscle relaxation
• Increasing diameter of blood vessel and
enhances blood flow
Viagra inhibits PDE5
• Phosphodiesterase degrades cGMP
into GMP
• Viagra inhibits PDE5 isoform
expressed primarily in penis
• End result is prolonged increased
levels of cGMP in smooth muscle
• allows increased blood flow into the
cavernous tissue of the penis thereby
generating an erection
Viagra™ started life as a medicine intended to treat angina
Alfred Nobel - an explosives manufacturer - suffered from angina.
In 1890 he was prescribed nitroglycerine (called trinitrin) to relieve
the pain of angina attacks. It is still used today.
Over 100 years later, the work of Robert Furchgott, Louis Ignarro
and Ferid Murad showed that nitric oxide (NO) was an important
signalling molecule in the cardiovascular system. It is released
from nerve endings and cells lining the walls of blood vessels. The
effect is to make the blood vessel relax, or dilate. It is also
involved in the prevention of blood clots. In 1998, they received
the Nobel Prize for Physiology. The Nobel prizes were set up by
the same Alfred Nobel who had been treated with nitroglycerine
Viagra was a failed anti-angina
9 types of PDE
• PDE5 is expressed in erectile tissue of penis
and in the retina
Giles Brindley and Drug Therapy for ED
Modern drug therapy for ED was advanced
enormously in 1983 when British physiologist Giles Brindley,
Ph.D. dropped his trousers and demonstrated to a shocked AUA
audience his phentolamine-induced erection. The drug Brindley
injected into his penis was a non-specific vasodilator, an alphablocking agent, and the mechanism of action was clearly corporal
smooth muscle relaxation. The effect that Brindley discovered,
established the fundamentals for the later development of specific,
safe, orally-effective drug therapies, ie, PDE-5 inhibitors.
Approved in 1998
G-Proteins in Photoreception