history of neurotransmission and introduction to ans
TRANSCRIPT
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History of neurotransmission and introduction
to ANSDr. Deepika G1st year PG
AIMS
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• Introduction• History of neurons and neurotransmission• Scientists and their experiments• Introduction to Autonomic nervous system• ANS Receptor functions • Physiological Effects of ANS• References
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Neurons And Synapses
• Until 1838 – Globules in the tissue.
• In Retrospect – 3 long steps.
1st Step : Discovery of neuron, dendrites and axons. 2nd Step : Neuron doctrine 3rd Step : Discovery of synapse and chemical transmission
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1st –Neurons, Dendrites and Axons1. Anton Van Leeuwenhoek (1632-1723) Built notable microscope, able to slice specimens of cow optical nerve(1674).
2. Robert Hooke (1635-1703) Used the word cell to describe smaller elements.
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3.Gabreiel Gustan Valentin (1810-1863) First to describe cell, nucleus, nucleolus of neurons(1836).
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4.Jan Evangelista Purkinje (1787-1869)• Studied nuerons in
cerebellum, coined term protoplasm.
• Described drop like cells have elongated fibre like processes in their vicinity -1837.
• Proposed that there should be some connection between these processes and nucleated cell bodies.
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5. Robert Remak (1815-1865)• Described nervous tissue is
entirely suffused with very fine and complex mesh of filamentous processes(1836).
• Described existence of two types of nerve processes- myelinated and unmyelinated
6. Theodor schwann(1810-1882)• Described myelin sheath
covers nerve fibres• Organic tissues are composed
of cells
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7.Alfonso Corti (1822-1876)• Obtained carmine red bright strain from
insects(1850).• Become famous for his descriptions of inner ear
organ of hearing which bears his name.8. Joseph Von Gerlach (1820-1886)• Obtained clearest
images of neural cells and its filaments.
• Improved fixatives for nervous tissue
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9. Otto Friedrich Karl Deiters (1834-1883)• Developed micro dissection
technique.• Isolated neurons under
microscope• Found two different branching
processes attached to soma Tree like full fine branching -protoplasmic extensions. Long fibre- axis cylinder.
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20 Years Later…Protoplasmic extensions Dendrites – Wilhelm His(1889)Axis cylinder Axons – Rudolph A Von Kolliker(1896)Cell Neuron – Wilhelm Von Waldeyer(1891)
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Second Big Step: Neuron Doctrine
SANTIAGO RAMON Y CAJAL (1852-1934)
CAMILLO GOLGI(1843- 1926)
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10. Camillo Golgi(1843-1926)
• Specific staining technique – The reazione nera (The black reaction).
• Exceedingly clear and well contrasted picture of neuron against an yellow background.
• Technique was unreliable as it didn’t stain all neurons.
• Defended Reticularist hypothesis
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11. Santiago Ramon Y Cajal (1852-1934)
• Improved Golgi technique - Used younger brains and brains of birds.
• Saw individual neurons and stated that no continuity between axons and neurons.
• Wilhelm His and Cajal gave embryological evidence about growth of neurons.
• Action currents propagate in neuronal network in direction of dendrites to axons/soma – Dynamic Polarisation.
• Increase in number of synapses could be mechanism of learning and memory.
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THE NEURONAL DOCTRINE HAD FOUR TENETSThe neuron is the structural and
functional unit of nervous system. Neurons are individual cells, which are
not continues to other neurons. The neuron has three parts : Dendrites,
Soma, Axon. Conduction takes place in direction from
dendrites to soma, to the end arborization of the axon.
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3rd STEP:Discovery of SYNAPSE &
Neurotransmission12. George Palade - Morphological proof of synapse (1954).13.Emil Dubois Raymond - Existence of synapse, could be electrical or chemical (1846). Unidirectional flow of information. Excitatory and inhibitory synapses. Delay in transmission.
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14. John Newport Langley (1852-1925) Coined the term autonomic nervous system. Discovered function of sympathetic and parasympathetic components. Laid foundation for humoral neurotransmission and concept of receptor substance.Action of jaborandi(Pilocarpine) on heart - 1875
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Deduced that pilocarpine slowed heart rate by acting on inhibitory fibres in vagus nerve to the heart, stimulated salivation.With Dickinson Nicotine has ganglion blocking property – 1889. With sherrington established distribution of sympathetic fibres innervating skin and relation with sensory fibres of associated spinal nerve- 1890. Leewandowsky(1889) and Langley(1901) noted independently the similarity between effects of injection of extract of adrenal gland and stimulation of sympathetic nerves.
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15. Sir Charles S Sherrington (1852-1952) Coined the term SYNAPSE- To Clasp Physiology of simple and complex motor reflexes – concept of integrative action of the nervous system. Interplay of central excitation and inhibition are fundamental for the integration – Awarded Nobel prize 1921.
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16. Thomas Renton Elliot (1877-1961) Concept of chemical neuro transmission. Demonstrated effects of sympathetic innervation and exogenous epinephrine on bladder. Adrenaline chemical stimulant liberated on each occasion when impulse arrived at the periphery – 1904. Postulated epinephrine acted at myoneural junction not at the nerve endings or muscle fibres.
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17. Walter Ernest Dixon(1871-1938)Interested in effect of drugs on nerves & nerve endings Opposed Erhlich statement
and showed that strychnine was not bound , while it acted at the site
Investigated action of vagus nerve on heartArgued against retention of heroin in
clinical practicePracticed to induce labour, showed that ovarian secretion caused uterine contraction via an indirect effect by release of pituitrin
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18. Sir Henry Hallet Dale(1875-
1968)• Distinguished muscarinic and nicotinic
receptor• First to identify acetylcholine(1914)• Proposed term cholinergic and adrenergic
synapses• Dale’s law: each neuron releases only one
type of neurotransmitter.• Dale’s vasomotor reversal phenomenon:
only fall in BP occurs when an alpha blocker is given before injecting adrenaline. He demonstrated in cats and used ergot alkaloids as alpha blockers.
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Two kinds of effects produced by Ach. A. Ach causes a fall in BP due to vasodilation.B. A larger dose of Ach also produces bradycardia, further reducing BP.C. Atropine blocks the effect of Ach in lowering BP.D. Still under the influence of atropine, a much larger dose of Ach causes a rise in BP and tachycardia.
Sir Henry Hallett Dale(Nobel laureate, 1936)
A, B: Muscarinic effects of Ach (M3, M2)C: Muscarinic antagonistic effect (M)D. Stimulation of sympathetic ganglia (NN)
(Arterial pressure of ananesthetized cat wasmeasured)
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19.Otto Loewi (1873-1961)• Proved the chemical
transmission of the nerve impulses and received Nobel prize with Henry Dale
• Idea of experiment in a dream and become a prototype for all investigations of chemical factors in the nervous system.
• Coined term Neurohumoral transmission
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• Findings of Experiment:
1. stimulation of vagus caused appearance
of a substance in perfusated heart capable
of producing in the second heart, an
inhibitory effect resembling vagus
stimulation.
2. stimulation of sympathetic nervous
system caused appearance of a substance
capable of accelerating the second heart,
later concluded that substance was
adrenaline.
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3.Atropine prevented the inhibitory action of
vagus on the heart but did not prevent
release of vagusstof.
4.physostigmine(eserine) potentiated the
effect of vagus stimulation on the heart,
prevented destruction of vagusstof by heart
muscle, due to inhibition of cholinesterase
which normally destroys acetylcholine.
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20.Wilhelm Feldberg & Otto Krayerfirst long experiment on role of AchStimulated vagus nerve of dog and cat, measured Ach in venous outflow of hearteffect of parasympathetic out flow in contraction of tongue muscle
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21.Walter Bradford Cannon(1871-1945): Discovery of adrenaline & concept of autoreceptor• With Uridil: stimulation of
sympathetic hepatic nerve in mammals release adrenaline like substance that increase blood pressure and heart rate.
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• With Bacq: idea of Autoreceptor• With Rosenblueth: hepatic nerve
stimulation caused rise in BP which persisted after administration of ergotoxin
• Sympathin E- excitatory effects• Sympathin I- inhibitory effects of
adrenaline• Studied effects of pituitrin on uterus
and practiced to induce labour.
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22.Ulf Von Euler(1905-1983):• Discovered active biological
agent from intestine: substance P
• Prostaglandin & vesiglandin-1935, piperidine-1942, noradrenaline-1946• Studied about NA distribution in nerves &
organs, excretion during various physiological and pathological conditions
• Researched about uptake, storage and release from nerve granules as well as neurotransmission process.
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23.Raymond Ahlquist (1914-1983)• Effects of adrenaline, noradrenaline & isoproternol in variety of target tissues.• In 1948 divided adrenoceptors into α- and β-adrenoceptor subtypes
• The pharmacology of the sympathetic nervous system.
• In 1958, dichloroisoprenaline the first clinically useful beta-blocker.
• Discovered that the peristalsis is enhanced by α-adrenoceptors and conversely inhibited by β-adrenoceptors.
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• Nobel Laureate, 1970
• His discoveries concern the
mechanisms which regulate the
formation of norepinephrine in
the nerve cells and the
mechanisms which are
involved in the inactivation of
this important neurotransmitter.
24. Julius Axelrod (1912-2004)
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25. Sir Bernard Katz:• Study of neuromuscular
junction with intracellular electrodes, role of Ach in synapse was demonstrated.
• Discovered that small fluctuations in basement membrane potential due to release of synaptic vesicles
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26. Sir John Carew Eccles:• Believed that
Synapses had electrical transmission
• 1951-Inserted microelectrodes into nerve cells , recorded electrical responses produced by synapses
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INTRODUCTION TO AUTONOMIC
NERVOUS SYSTEM
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Neurohumoral Transmission
• Nerves that transmit their message across synapses and neuroeffector junctions by release of humoral (chemical) messengers.
• Criteria's for transmitter :a. Presynaptic neurone with synthesizing
enzymesb. Released following nerve stimulationc. Produce response identical to nerve
stimulated responsed. Potentiated or antagonized by other
substances
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Steps Of Neurohumoral Transmission
I. Impulse conduction: Resting transmembrane potential -70mv,high k+ & low Na+ concentration,Impulse ↑↑↑Na+ depolarize overshoot,+20 mvNormalize by activation of Na+ K+ pump.II. Transmitter ReleaseStored in vesicles prejunctionally,Fusion of vesical & axonal membrane through Ca+ influx.
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III. Transmitter action on post junctional membraneEPSP: increase in cation permeability depolarisation followed k+ effluxIPSP: increase anion permeability hyperpolarisationIV. Post junctional activityV. Termination of transmitter action: parasympathetic Ach- hydrolyzed by AchE VIP- degrades by peptidases sympathetic NA- acts at junction, diffuses & recycles NPY- diffuses & degrades Gaba-ergic GABA- acts , diffuses & recycles
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• Graded in magnitude
• Have no threshold
• Cause depolarizationo Movement of
Na+ and K+• Summate• Have no
refractory period
Excitatory post synaptic
potential
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Inhibitory Post Synaptic Potential
• Cause hyperpolarizationoK+ or Cl-
• Small in magnitude
• Makes membrane less excitable
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Synthesis & Storage
Actionpotential
Metabolism
Recognition(action)
Key Steps in Neurotransmission:
Strategies for Pharmacological Intervention:
Block synthesis and storage: Usually rate-limiting steps; produce long- term effectsBlock release: Rapid action and effectiveBlock reuptake increases synaptic neurotransmitter concentrations Can be selective or non-selectiveInterfere with metabolism: Can be reversible or irreversible; blocking metabolism
increases effective neurotransmitter concentrationsInterfere with recognition: Receptor antagonists & agonists; high specificity
Release
Reuptake
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Parsympathetic Nervous System
• Cholinergic system• Craniosacral out flow- CN III, VII, IX, X &
S2,3,4• Preganglionic fibres myelinated, long• Post ganglionic fibres non myelinated, short• Parasympathetic ganglia: ciliary ganglia Sphenopalatine ganglia, submaxillary ganglia, otic ganglia.• EXCEPTION: ciliary post ganglionic
fibres are myelinated
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PARA SYMPATHETIC
NEUROTRANSMITTERS:
Acetylcholine(Ach)- Neurotransmitter
a. Somatic motor neuron to skeletal muscle(NMJ)
b. Preganglionic parasympathetic/ sympathetic fibres
c. Post ganglionic parasympathetic fibres to NEJ
EXCEPTION: postganglionic sympathetic fibres to
sweat glands of palm and sole are cholinergic
Hypothalamus is major controlling centre for PNS
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Synthesis of acetylcholine:
CH3
CH3
CH3
N+–CH2–CH2–OH
CoA–S–C–CH3
O
Choline
Acetyl-CoA
+
Cholineacetyltransferase
CH3
CH3
CH3
N+–CH2–CH2–O–C–CH3
O
CoA-SH
+
CoA
Acetylcholine
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Synthesis, storage and release of acetylcholine:
Pre-synapticcell
Post-synapticcell
Ach
Ca2+
Na+
Choline(10 mM)
Choline
Recognitionby receptors
Ca2+
Ach
Ach
Ach
Nerveimpulse
NN
NM
AchAc-CoA
ChAT
Ach
AchE
AchE
choline+ acetic acid
CAT = choline acetyltransferaseAchE = acetylcholinesterase
Synapticcleft
Antiporter
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CH3COOH+AchE
(CH3)3 N+–CH2–CH2–OH(CH3)3 N+–CH2–CH2–O–C–CH3
OH2
O
OH(-)AchE
Glu202Tyr337
Ser203Glu334His447
Degradation of acetylcholine:
Steps involved in the action of acetylcholinesterase:
1. Binding of substrate (Ach)
2. Formation of a transient intermediate (involving -OH on Serine 203, etc.)
3. Loss of choline and formation of acetylated enzyme
4. Deacylation of AchE (regeneration of enzyme)
600,000 Ach molecules / AchE / min= turnover time of 150 microseconds
Choline Acetic acid
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Sympathetic Nervous System
• Adrenergic system• Thoracolumber outflow• Preganglionic neurons leave spinal nerve
and communicate with paravertebral chain of 22 sympathetic ganglia
• 3 cervical and sacral ganglia run upward or downward making no synapse in between
• T1- T4 preganglionic fibres synapse with post ganglionic fibres in paravertebral ganglia
• T5-T11 preganglionic fibres -Coeliac ganglia
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• T12-L1 preganglionic fibres - superior mesentric ganglia.
• L2-L3 preganglionic fibres- inferior mesentric ganglia.
• T10- T11 some preganglionic fibres terminate in chromaffin cells of adrenal gland i.e no post ganglionic fibres.
• Pre ganglionic fibres: myelinated , shorter or equal with post ganglionic fibres
• Post ganglionic fibres: non myelinated• Vasomotor centre in major controlling
centre for SNS.
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SYMPATHETIC NEUROTRANSMITTERS:• Neurotransmitter at sympathetic ganglia is
acetylcholine• Sympathetic post ganglionic fibres release
Norepinephrine(NE) at neuroeffector junction.• EXCEPTION:i. Postganglionic sympathetic fibres to sweat
glandii. Some post ganglionic sympathetic fibres to
arterioles of skeletal muscle iii. Some post ganglionic sympathetic fibres at
splanchnic and renal blood vessels are dopaminergic in nature.
iv. Preganglionic sympathetic nerve fibres to adrenal medulla neurotransmitter is Ach but on stimulation cells secrete Epinephrine.
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HO
HO
CH2
NHCH3
OH
CH
Epinephrine
HO
HO
CH2
NH2
OH
CH
NorepinephrineHO
HO
CH2
NH2
CH2
Dopamine
HO
HO
HC
NH2
CH2
DOPA
COOHHOHC
NH2
CH2
Tyrosine
COOH
TH
DD (L-AAD)
DBH
PNMT
Adrenal medulla
Synthesis of Catecholamines
Tyrosine hydroxylase
Dopa decarboxylase (L-amino acid decarboxylase)
Dopamine b-hydroxylase
N-methyl transferasePhenylethanolamine-
13
L-phenylalanine
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Pre-synapticPost-synaptic
Ca2+
Na+
Tyrosine
Cellular messengersand effects
Diffusion, metabolism
Tyrosine
Dopa
TH
DDDopamine(DA)
NE
DBHATP
Ca2+
NE
DBHATP NE
NE
COMT
aR
bR
a2R
NE
(-)
Signal
Regulation of Norepinephrine Synthesis and Metabolism:
Uptake-1
Normetanephrine (NMN)
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Rules & Exceptions of Autonomic
innervations• Parasympathetic nervous system: energy
storing and restorative system• Sympathetic nervous system: Prepares for
E- situations i.e.. Emergency, exercise, embarrssment
• Only sympathetic no parasympathetic innervations:
radial muscle of iris, smooth muscle of eyelids, nictating membrane pilomotor muscle, ventricular myocardium bladder neck(trigone), seminal vesical & vas deferens
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• Only parasympathetic no sympathetic innervations:
circular muscles of iris, ciliary muscle lacrimal glands, mucus membrane of GIT bronchial tree, pancreatic exocrine glands detrusor muscle of bladder, erectile tissue of penis• Only Adrenergic receptors no sympathetic
innervations: Adipocytes – lipolysis Liver cells –gluconeogenesis, skeletal muscle cells –glycolysis
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• Only cholinergic receptors no parasympathetic inervations:
Blood vessels• Sympathetic in nature but cholinergic in
character: Sweat galnds, arterioles of skeletal muscles• Sympathetic system is antagonist to
parasympathetic system: On salivary glands its stimulatory
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PNS RECEPTOR FUNCTIONS
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PNS Receptors - Pharmacological Classification:
Cholinergic R
Adrenergic R
Dopamine R
Muscarinic R
Nicotinic R
M1, M3, M5 (Gq coupled)
M2, M4 (Gi coupled)
NM (neuromuscular, or muscle type)
NN (neuronal, or ganglion type)
b1,
a2a1,
b2, b3
D1, D2, D3, D4, D5
Other receptors (receptors for NANC transmitters,e.g. nitric oxide, vasoactive intestinal peptide, neuropeptide Y)
(mAChR)
(nAChR)
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“Nicotinic actions” -- similar to those induced by nicotine; action mediated by nicotinic cholinergic receptors:
• stimulation of all autonomic ganglia (NN)• stimulation of voluntary muscle (NM)• secretion of epinephrine from the adrenal medulla (NN)
Cholinergic receptors: Nicotinic
Nicotiana tabacum(cultivated tobacco)
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Nicotinic acetylcholine receptor: Function
Ligand-gated ion (Na+) channel - an “Ionotropic Receptor”
• Acetylcholine binds to the α-subunits of the receptor making the membrane more permeable to cations (Na+) and causing a local depolarization. The local depolarization spreads to an action potential, or leads to muscle contraction when summed with the action of other receptors. The ion channel is open during the active state. • Nicotine in small doses stimulates autonomic ganglia and adrenal medulla. When large doses are applied, the stimulatory effect is quickly followed by a blockade of transmission.
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“Muscarinic actions” -- reproduced by injection of muscarine, from Amanita muscaria (fly agaric). Similar to those of parasympathetic stimulation
Cholinergic Receptors: Muscarinic
Multiple muscarinic cholinergic receptors distributed in different tissues. Therefore, the “muscarinic actions” are dependent on the receptors in different tissues and cells.
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• Neural/enteric (M1): CNS, ENS, gastric
parietal cells (excitatory; Gq)
• Cardiac (M2): atria & conducting tissue;
presynaptic (inhibitory; Gi)
• Glandular/endothelial (M3): exocrine
glands, vessels (excitatory; Gq)
• Neural (M4): CNS (inhibitory; Gi)
• Neural (M5): CNS (excitatory; Gq)
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Agonist
Muscarinic acetylcholine receptors –G Protein-Coupled Receptors (“Metabotropic” Receptors)
Agonist
M1(enteric, neuronal)
M2(cardiac)
M3(glandular, vascular )
Gq Gi
IP3, DAG
(Depolarization)
(Stimulation)
Intracellular Ca2+
cAMP
Ca2+ channel
K+ conductance K+ conductance
Mostly excitatoryCNS excitationGastric acid secretionGastrointestinal motility
Mostly inhibitoryCardiac inhibitionPresynaptic inhibitionNeuronal inhibition
Glandular secretionContraction of visceral smooth muscleVasodilation (via NO)
(Slow IPSP)
(Inhibition)
M5(CNS)
M4(CNS)
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Intracellular signaling triggered by acetylcholine in the Heart
Main molecular players: M2, heterotrimeric G Protein Gi, Adenylyl cyclase
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Clinical manifestation of excessive cholinergic effects
D – DefecationU – Urination M – MiosisB – BradycardiaE – EmesisL – Lacrimation S – Salivation
(DUMBELS)
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Classification of adrenergic receptors by agonist potency
a -- NE Epi > Iso
b -- Iso > Epi > NE
NE = norepinephrineEpi = epinephrineIso = isoproterenol
HO
HO
CH2
NHCH3
OH
CH
Epi
HO
HO
CH2
NH2
OH
CH
NE
HO
HO
CH2
NH
OHCH
IsoCH(CH3)2
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Agonist
Signaling properties of adrenergic receptors
AgonistAgonista1 a2 b1,2,3
Gq Gi Gs
Inositol phosphates (IP3)
Diacyl glycerol (DAG)
cAMP cAMP
Calcium channels
K+ conductance
Mostly excitatory Mostly inhibitory Mostly excitatory
NorepinephrineEpinephrinePhenylephrine
NorepinephrineMethyl NEClonidine
IsoproterenolAlbuterol (b2)Dobutamine (b1)
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Gs and Gi proteins have different functions
Agonist
bg as
Agonist
bgai
AC
asbg
ai bg
Gs = stimulatory G protein
Gi = inhibitory G protein
AC = adenylyl cyclase (convert ATP to cAMP)
Beta1 receptor Alpha2 receptor
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a1: Postsynaptic effector cells, especially smooth muscle, salivary glands, liver cells
Vasoconstriction, relaxation of intestine, salivary secretion, hepatic glycogenolysisa2 : Presynaptic adrenergic nerve terminals (autoreceptor), platelets, lipocytes, smooth muscle, β pancreatic cells
Inhibition of transmitter release, platelet aggregation, contraction of vascular smooth muscle, inhibition of insulin release
Distribution and Functions of Adrenergic Receptors:
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b2 : postsynaptic effector cells: smooth muscle, cardiac muscle,coronary arteries
Bronchodilation, vasodilation, relaxation of visceral smooth muscle, hepatic glycogenolysis
b1 postsynaptic effector cells: heart, lipocytes, brain, presynaptic adrenergic / cholinergic terminals, juxtaglomerular apparatus
Increased heart rate & force of contraction, increased renin release
3b postsynaptic effector cells: lipocytesLipolysis
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HO
HO
CH2
NHCH3
OH
CH
Epinephrine
HO
HO
CH2
NH2
OH
CH
Norepinephrine
HO
HO
CH2
NH2
CH2
Dopamine
HO
HO
HC
NH2
CH2
DOPA
COOHHO HC
NH2
CH2
Tyrosine
COOHTH
DD (L-AAD)
DBHPNMT
Tyrosine hydroxylase
Dopa decarboxylase (L-amino acid decarboxylase)
Dopamine b-hydroxylase
Phenylethanolamine-N-methyl transferase
13
Dopaminergic receptors
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Dopaminergic receptors in the periphery
Dopamine receptors play important roles in CNS. Notably, dopamine neurotransmission is involved in several diseases including Parkinson’s disease, schizophenia, and attention deficiency disorder.
There are 5 types of dopamine receptors (D1 – D5). In
periphery, D1 dopamine receptor mediates renal vasodilation, and increased myocardial contractility.
Agonist Agonist
D2,3,4D1,5
GiGs
cAMP cAMP
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Physiological Effects of ANS
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Receptor distribution and effects in the autonomic nervous system:
Organ Receptor Parasympathetic Receptor
Heart
RateForce Automaticity
Automaticity Force
1b1
b1
b1
b1
Rate Force Conduction velocity AV block
M2
M2
M2
Arterioles
SA nodeAtrial muscleAV node
Ventricular muscle
Blood vessels
CoronarySkeletal muscleVisceraSkinBrainErectile tissueSalivary gland
ContractionRelaxationContractionContractionContractionContractionContractionContractionRelaxation
a1
b2
a1
a1
a1
a1
a1
a1
b2
RelaxationRelaxation
Vein
M3
M3
Sympathetic
(Continued, next page)
M3
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Organ Sympathetic Receptor Parasympathetic Receptor
Relaxation
Motility Contraction
ContractionRelaxation
Viscera
Bronchiolar SMC GlandsGI track Smooth muscle Sphincters Glands
Uterus
a2,b2
a1
1ab2
Secretion
Motility RelaxationSecretionGastric acid secretion
Variable
M3
M3
M3
M3
M1
Skin Pilomotor SMC Contraction (piloerection) 1a
Salivary glands Secretion a1,b1 Secretion M3
Lacrimal glands Secretion M3
Kidney Renin release b1
Liver GlycogenolysisGluconeogenesis
2, 1b a2, 1a
b2
Fat Lipolysis b3
M3Contraction
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Cardiovascular Pharmacology(Blood Pressure)
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Cardiovascular effects of intravenous infusion of epinephrine, norepinephrine, and isoproterenolin man. Norepinephrine (predominantly a-agonist) causes vasoconstriction and increased systolicand diastolic BP, with a reflex bradycardia. Isoproterenol (b-agonist) is a vasodilator, but stronglyincreases cardiac force and rate. Mean arterial pressure falls. Epinephrine combines both actions.
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Intracellular signaling triggered by acetylcholine in the endothelium
eNOS
●NO
L-Arg
L-Citruline
Major molecular players: M3, heterotrimeric G Protein Gq, Ca(2+)-CaM, eNOS, NO
eNOS Nitric oxide synthase
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Nitric oxide (NO) signaling pathway for SMC relaxation
Secondmessenger
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Pulmonary Pharmacology(Asthma and COPD)
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Ocular Pharmacology(Glaucoma)
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Lens
Pupillary dilator muscle ( 1a )Pupillary constrictor muscle (M3)
Secretion of aqueous humor (b)(M3)
Cholinergic effects: Adrenergic effects:
• Contraction of pupillary constrictor muscle-- miosis• Contraction of ciliary muscle - bulge of lens-- near vision, outflow of aqueous humor
• Contraction of pupillary dilator muscle-- mydriasis• Stimulation of ciliary epithelium-- production of aqueous humor
Trabecular meshwork
(opened by pilocarpine)
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Enteric nervous system
• Collection of well organised neurons in wall of GIT with pupose of controlling its functions
• Integrative capability to function independently of CNS
• Major network of nerve fibres myentric (Auerbach’s) plexus: between longitudinal and circular muscle layers submucosal (meissner’s) plexus: between circular muscle layer and the mucosa• Nuerotransmitters: Ach, NE,
neuropeptide, substance P, serotonin, dopamin, cholecystokinin.
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References:• Goodman & Gilman’s The pharmacological basis
of therapeutics: 10th 12th edition• Rang and Dale’s pharmacology: 6th edition• Sharma & Sharma’s principles of pharmacology:
1st edition• KD Tripathi’s essentials of medical
pharmacology: 7th edition• Katzung’s basic &clinical pharmacology:12th
edition• Golan’s principles of pharmacology: 3rd edition• Internet sources….
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