Introduction to Autonomic Pharmacology part 2 Flashcards
What happens to the NE that is taken back into the cell
its repackaged into vessicles by the vescular monoamine transporter
What is MAO and COMT
MAO is know as monoamine oxidase
COMT is known as catechol-O-methyltransferase
What does MAO do
deaminate NE, Epi, and dopamine
Where is MAO located and what is its form
its located on the outer surface of the mitochondria
it has two forms: A and b
If MAO is inhibited what happens
inhibitiors elevate levels of the neurotransmitters in the synapse and are useful in treating depression, Parkinson’s disease and other CNS diseas
What is COMT and where is it located
an enzyme, its found in the cytoplasm of the liver cells and is involved in the metabolism of endogenous circulation and administed catecholamines by O-methylation reaction
What is the function of COMT
its involved in the metabolism of endogenous circulating and administered catecholamines by O-methylation reaction
What is the mechanism of transmitter release
- the priniciple way is exocytosis– the neutrotransmitter is stored in intracellular vesicles
- vesicles fuse transiently with cell membrane and discharge their contents, in response to increase in intracellular Ca2+ concentrations
- monoamine transmitters leak out by carrier mediated transport as well as NO and a.a. metabolites can diffuse
What are parasypathetic and sympathetic nerve varicosities
in the autonomic nervous system—long thin axons that are branched and have small enlargements or varicosities
What is the function of varicosities
neurotransmitter is synthesized and stored in caricosities- 20,000 per neuron and release the transmitters into the extracellular space
What happens to neurotransmitters after they are released from varicosities
they diffuse through extracellular space and affect many effector tissues cells: one neurone is capable of innervating an entire organ
What is non-adrenergic non-cholinergic transmission
that autonomic transmision can not be completely blocked by drugs that abolish response to NE or Epi because there are many other mediator secreted
How was it determined that there were more transmitters than NE and Epi
by fluorescence and immunocytochemical methods
What are the most common transmitter substance; but what are the other kinds
peptide are the most common transmitter substance but ATP and purines are also present; neurons contains as many as five different possible transmitters
What is the most extensively studied system containing NANC neurons
the enteric system in the gut wall ( in addition to cholineric and adrenergic fibers)
What is the rule of NANC transmission
co-transmission is the rule rather than the exception–release of more than one neurontransmitter from the same neuron
What is the location and function of neuropeptide Y, ATP, Dopamine, Enkephalin and related opoid peptide
*neuropeptide Y–
location: secretomotor neurons in the ENS
function:
1) inhibit the secretion of water and electrolyytes by the gut
2) causes long lasting vasconstriction
3) cotransmitter in many parasympathetic postganglionic neurons
4) sympathetic postganglionic noradrenergic vascular neurons
*ATP (adenosine triphosphate)—
location: cotransmitter at inhibitory ENS neuromuscular junctions
function:
1) inhibits release ACh and norepinephrine from ANS nerve endings
2) excitatory transmitter in the nerves of the vas deferens
*Dopamine
location: important postganglionic sympathetic transmitter in renal blood vessels
function:
1) a modulatory transmitter in some ganglia and the ENS
*Enkephalin and related opoid peptide
location: some secretomotor and interneuron in the ENS
function:
1) inhibit the ACh release and thereby inhibit peristalsis; may stimulate secretion
What is the location and function of galanin, CCK, CGRP, GABA, GRP, and NO
–Galanin:
Location: present in secretomotor neuron
Function: may play a role in appetit-saitety mechanisms
–Cholecystokinin
Function: acts as a cotransmitter in some excitatory neuromusclar ENS neurons
—Calcitonin gene related peptide (CGRP)
Location: in the substance P in cardiovascular sensory nerve fibers, some secretomotor ENS neurons and interneurons
Function: a cardiac stimulant
—GABA ( gamma-aminobutyric acid)
Function:
1) presynaptic effects on excitatory ENS nerve terminals (not a major transmitter in the ENS)
2) relaxant effect on the gut
—gastrin releasing peptide (GRP)
Function: extremely potent excitatory transmitter to gastrin cells; known as mammalian bombesin
—NO (nitric oxide)
Function: co-transmitter at inhibitory ENS neuromuscular junction; important at sphincters
What is the location and function of 5-HT, substance P, and VIP
5-HT (Serotonin)::
Function: co-transmitter at inhibitor ENS neuromuscular junctions; important at sphincters
Substance P (and related “tachykinins)::
Location: an important sensory neuron transmitter in the ENS and elsewhere
Location: CGRP in cardioivacular sensory neurons
“tachykinins”- excitaory cotransmitters with ACh at ENS neuromuscular junctions
What is neuromodulation of synaptic transmisssion
its control of transmission of different levels such as autoreceptors and heteroreceptors
What are autoreceptors and how do they work
neurotransmitters may act upon autoreceptors present on the presynaptic terminal to modulate its own release and uptake process
What are heteroreceptors and how do they work
its a receptor regulating the synthesis and/or release of mediator other than its own ligand.
for example a2 receptors found presynaptically on cholinergic neurons activation by NE results in inhibition of ACh release
How do the autoreceptors on cholinergic neurons work
heteroreceptors–the cholinergic neuron which releases ACh has an alpha-2 sympathetic receptor
How does the receptor modulate the release of neurotransmitters
What is another way to modulate synaptic transmission
by altering ion currents either hyperpolarize (elevate threshold) or depolarize (decrease threshold) of the axon terminal
Of activation of second messenger systems such as cAMP or cGMP can lead to phosphorylation of various protein involved in the activity of the acon terminal such as transporters and vesicle proteins
Explain the schema of presynaptic autoreceptors
regulate neurotransmitter release in adrenergic (release NE) and cholinergic neurons (ACh)
A2 and B2- adrenergic receptors exist on post sympathetic nerve terminal and inhibit the release of the neurotransmitter, NE
Muscarinic and nicotinic cholinergic receptors exist on postganglionic parasympathetic neuron that block release ACh. A2 adrenergic receptors also exist cholinergic neurons and inhibit Ach release–for
adrenergic neurons (those that release neurotransmitters that go to adrenergic receptors)–NE
cholinergic neurons (those that release neurotransmitters that go to cholinergic receptors)–ACh
What are the two main types of Ach receptors
muscarinic and nicotinic receptors
What is the alkaloid muscarine and where does it work; how is the name muscarine receptors fitting
the poisonous agent in toadstools-Amanita muscaria- they have little to no effect on receptors in autonomic gangia but mimics the action of ACh on the effector of smooth muscle
therefore the actions of ACh on SM effector organs and on heart muscle are known as muscarinic and the receptors are know as muscarinic receptors
What are cholinergic receptors
these are the ACh receptors can be divided into two main types: muscarinic and nicotinic receptors
Why is the name nicotinic receptors fitting and how does blocking muscarinic receptors help
in the autonomic ganglia, the actions of ACh can be reproduced by the drug nicotine. The actions of ACh in sympathetic ganglia are referred to as nicotinic, the receptors are known as nicotinic receptors
by blocking the muscarinic effects and then larger doses of ACh produce nicotinic effects. In addition with ganglionic effects, stimulation of voluntary muscle and simulation of Epi secretion from the adrenal medulla is also observed
What are the effects of Ach on nicotinic receptors
nicotinic receptors are located where quicker responses are needed (adrenal gland)
found in sympathetic and parasympathetic postganglionic neurons at neuromuscular junctions of skeletal muscles, and at some cholinergic synapses in the central nervous system
What type of effects was seen with acetylcholine on the cat’’s blood pressure
ACh causes a fall in blood pressure due to vasodilation, larger doses produce bradycardia—these are muscarinic effects
What are the two types of cholinergic receptors
nicotinic and muscarinic
What are the nicotinic receptors and what is their neutrotrasmitter
nicotinic ACh receptors are ligand-gated ion channels that are composed of multiple subunits (a pentamer w/’ 1-4 distinict subunits–subunits around an internal channel)
How do nicotinic receptors work, describe using the diagram
two ACh molecules bind to the receptor to cause the Na+ channel to open
the Na+ increase with the cell, an action potential is generated leading to a response
What are the two subtypes of nicotinic receptors
two subtypes of nicotinic receptors:
1) Nm found @ sketeletal muscle and neuromuscular junction
2) Nn which is neuronal subtype (ganglia and adrenal gland)
What are muscarinic receptors and what is their neurotransmitter
G-protein coupled receptors that exhibit classical 7 transmembrane topology and activates second messengers
What are the five muscarinic receptor subtypes
M1-M5 subtypes of muscarinic receptors
How do M1, M3, M5 work (odd numbers)
the M1, M3, M5 are coupled to the stimulation of IP3/ DAG pathway via Gq
How do M2 and M4 work (even numbers) and what is imporatant about M2 receptors
M2 and M4 are coupled to inhibition of cAMO production via an inhibitory G-protein
M2 receptors are coupled to elevation of K+ excretion which lead of hyperpolarization via a G-protein
What is the difference between nicotinic and muscarinic receptors; which is slower and what is this important
the difference is their speed of action; nicotinic receptors produces almost instantaneous responses and muscarinic receptors results in slower but more prolonged effects (why muscarinic receptors results in slower but more prolonged effects
Summarize the location and function of nicotinic receptors
nicotinic receptors are located where quicker responses are needed (adrenal gland); nicotinic receptors are found in sympathetic and parasympathetic postganglion neurons, at neuromuscular junctions of skeletal muscles, and at some cholinergic synapses in the central nervous systems
Summarize the location and function of muscarinic receptors
found primarily in the membranes of visceral effectors, example in the heart, gastro-intestinal track, arterioles of genitalia, iris of the eye, salivary and sweat glands, lungs airways and urinary bladder
Or rare occasion what can Ach interact with what receptors
although the primary receptors at the ganglia is nicotinic can have M1 receptors; ACh interacts with Nm receptors but on rare occasions can interact with minor M1 (muscarinic) receptors
What are the adrenergic receptors
receptors where epinephrine, norepinephrine, isoproteranol work on; a multitude of subfamilies and subtypes of adrenergic receptors have been identified, alquist made the first differentiation of subfamilies
What is the order of the adrenergic agonist
potency of adrenergic agonists in the stimulation of smooth muscle contration in vasculature was:
epinephrine> norepinephrine> isoproteranol (alpha receptor mediated)
for the same agonist, the rank order of potency for stimulation of heart rate was:
isoproteranol> epinephrine> norepinephrine (beta receptor mediated)
What is the rank order of potency for stimulation of heart rate
isoproteranol> epinephrine> norepinephrine
its beta receptor mediated
How is the response of the vasculature classified compared to the heart
its classified as alpha-receptor mediated
What molecular tool allowed for classification of alpha and beta receptors
advent of more selective compounds and the tools of molecular biology have greatly expanded these obeservation of alpha and beta receptor mediated–and even more specific sub-classification of alpha and beta receptors
How do the adrenergic receptors work
all adrenergic receptors are G-protein coupled and therefor activate second messengers but they differ in which second messengar they activtate, their tissue distrbution, DNA sequence and their pharmacological profile
How are beta adrenergic receptors classified
classified into three subtypes: beta1, beta2, and beta3
all three subtypes are coupled to the activation of cAMP via Gs—> cAMP the activates protein kinase A which can phosphorylate various proteins to either activate or inhibit them
What is the activation of beta-adrenergic receptors coupled to?.
activation of cAMP via Gs
Compare the sensitivity of alpha receptors and beta receptors to which neurotransmitter
alpha receptors stimulated mostly by NE
beta receptors more sensitive to epinephrine
What is the rule if alpha and beta receptors are both present; give an example
Rule: if alpha and beta receptors are present
alpha= excitation
beta= inhibition
For example, in skeletal muscle’s arterioles, norepinephrine secreted by post-ganglionic neurons—> vasoconstriction by alpha receptors (excitation)
beta-2 receptors stimulated by circulating Epi—> vasodilation (inhibition)
What is an exception of the beta and alpha receptor rule
exceptions: beta-1 receptors stimulate heart to beat faster and stronger contraction; muscarinic-2-receptors decrease strength of contraction
What are types of the alpha adrenergic receptors
alpha-1 and apha-2
What are the subtypes for alpha-1- receptor and how do the pathways waork
there are 3 subtypes of alpha 1 receptors: 1A, 1B, 1D all of which are coupled to the activation of IP3 / DAG pathway—> DAG can activate PKC and subsequent protein phosphorylation—-> IP3 can elevate intracellular Ca2+ level
What are the subtypes for alpha-2-receptors and how do the pathways work
there are 3 subtypes of alpha receptors: 2A, 2B, and 2D
2A and 2B decrease intracellular Ca2+ levels
2A elevates K+ conductance (hyperpolarizing)
Explain ocular pharmacology
