Physiology 3140A Lecture Notes - Lecture 4: Nicotinic Acetylcholine Receptor, Fluorescent Tag, Thyroid Hormones
22 May 2018
School
Department
Course
Professor
Physiology 3140
Dr. Rylett
Lecture 4
Foreign Substances that act on cell surface receptors
- Normal state: endogenous ligand (except hot and cold) that our bodies make
o This is the normal signal that the receptor would receive and be able to communicate
- There are many other substances (ex: drugs/environmental substance) that also act through the
same receptors
- So there can be competition and confusion bc where the normal ligand may mediate the effect,
now all of the sudden you have an exaggerated or inappropriate effect occurring
- Ex: ACh binds to nicotinic receptors which causes change in conductance&gating of ion channels
o Ach also changes the diameter of blood vessels to alter BP
o This can be acted on by nicotine (smoking)
o Nicotine mimics ACh and leads to that same effect
- Ex: Ach binds to curare and leads to muscle contraction
o Curare (acts as antagonist = paralysis) also binds to the same receptor and antagonizes
Ach as the endogenous ligand and blocks its effect
- Same ligand can get very different biological effects depending on the tissue that the receptors is
expressed on
- Ex: capsaicin is found in hot peppers and can work through receptors that are temperature
sensitive
o Receptors that are normally stimulated by heat and cause us to be able to sense
temperature
o Capsaicin binding to these receptors can cause a large, exaggerated effect (burning
sensation, pain etc)
o If this becomes too prolonged, it can lead to an analgesic effect
- Some drugs are taken advantage of
o Ex: heat cold gels for sore muscles use menthol: activates same type of receptors to
induce a cool sensation
o Can get a combination of things = have a hot effect and then a cold effect = analgesia (do
not feel pain)
- POINT IS:
o you can have a substance that is not the endogenous substance in the body that then
activates the receptor
o this could be a drug or something that acts like a drug
- most drugs act as agonists or other as antagonists
o Agonist: substance that initiates physiological response when combined with a receptor
o Antagonist: substance that interferes with or inhibits the physiological action of another
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- Can tag receptors with fluorescent proteins (e.g. GFP)
o When a fluorescent tag is added onto a receptor, you can image the cell with a confocal
microscope and see where the receptor is in the cell
- In a resting cell, many receptors are seen at the cell surface
Activation of GPCR Signalling
- Receptors
o G protein-coupled receptors (GPCRs) form largest family of integral membrane receptor
proteins in humans just greater than 2% of genome
o estimated that more than 650 GPCRs - of this number ~ 300 encode olfactory receptors
o of remaining only 250 receptors have been ascribed endogenous ligands leaving 100
orphan receptors with no know function
o ~ 1/2 of all prescribed drugs target GPCRs either directly or indirectly.
o JUST KNOW THIS:
▪ A large proportion of the human genome encodes GPCRs
▪ almost half of those are olfactory receptors
▪ about 250 of them are endogenous ligands
• adrenaline, dopamine, serotonin, neurotransmitters, hormones
▪ theres a bunch of orphan receptors
• part of genome that encode GPCR (we know that based on the sequence
→has same structural features as GPCR)
• so we know they are receptors and can be tagged with GFP
• but we have no idea what the ligands are
• there is still a large number of GPCRs that we have no idea what the
ligands are, what the physiological function is, what drugs can be used
to modify their function
▪ about ½ of all prescribed drugs work on GPCRs
- Ligands
o enormous diversity in ligands that activate G protein-coupled receptors (GPCRs).
o GPCRs respond to ligands as diverse as light, smell, taste, hormones, neurotransmitters,
ions, nucleotides, small peptides, large glycoproteins, fatty acids, amino acids, and
pheromones.
o The ligands work in families
▪ There is not a single adrenaline receptor or a single Ach receptor
▪ The numbers are always changing because there are orphan receptors for which
we do not know the function for
▪ New receptors and new functions are constantly being discovered
o Receptors work in families
▪ there can be multiple receptors for an individual ligand
▪ Each of the receptors can have a different outcome
o the same ligand can activate multiple different receptors in the same family
o examples
▪ 9 distinct receptors are activated by adrenaline
▪ 5 receptors are activated by acetylcholine
▪ 7 receptors are activated by glutamate
▪ 15 receptors are activated by serotonin.
▪ Dont memorize these numbers
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find more resources at oneclass.com
Diversity of Physiological Responses
- dont memorize this chart
- just know the basic concepts
- you can look at the target tissue, hormone and response
- a receptor is connected to different intracellular signaling molecuels and pathways and that can
lead to a different output
- ex: ACTH
o if its binding to its family of receptors in adrenal cortex, it leads to cortisol release
o but in fat tissue, its involved in triglyceride breakdown (metabolism)
- TSH: involved in thyroid hormone synthesis secretion but also involved in triglyceride
breakdown
- Adrenaline: In muscle, its involved in glycogen breakdown but in heart its involved in regulating
heart rate and force of contraction
- SO TISSUE SPECIFIC RESPONSES, RECEPTOR SPECIFIC RESPONSES AND THEN THESE
RESPONSES ARE GOVERNED BY THE SIGNALING PATHWAY THAT THE PARTICULAR
RECEPTOR HAPPENS TO BE COUPLED TO
- The same receptor is also able to have multiple functions – bc may have diff intracellular
signaling pathways bc the end target they signal to is linked to diff biological function
Examples: Top selling drugs targeting GPCRs
- ½ of the drugs prescribed are directed to GPCRs
- histamine receptors
o in the gut, they are involved in ulcer development and inflammation
▪ drugs: zantac and Pepcid are antagonist of the histamine receptors and
treatments for ulccers
o in respiratory system, histamine receptors are involved in allergies
▪ drugs: clariton, allegra
- different receptors are expressed differentially in different tissue, same ligand but then different
drugs develop to be able to address those specific receptor subtypes in those specific tissue to
get out of specific physical conditions
- 5HT receptors
o deal with everything from psychosis to migraines (brain related things) but with
different outcomes
o tehse drugs have diff effects on diff 5HT receptors
- JUST KNOW THAT: subtypes of receptors are going to have different tissue distributions and the
same ligand can bind to those diff subsets of receptors in those diff tissues and can mediate diff
biological outcomes →so drugs can be targeted to that subtype of receptor
o So the drug company will be looking for what is the selectivity for the drug I want to
develop?
find more resources at oneclass.com
find more resources at oneclass.com
Document Summary
Foreign substances that act on cell surface receptors. Normal state: endogenous ligand (except hot and cold) that our bodies make: this is the normal signal that the receptor would receive and be able to communicate. There are many other substances (ex: drugs/environmental substance) that also act through the same receptors. So there can be competition and confusion bc where the normal ligand may mediate the effect, now all of the sudden you have an exaggerated or inappropriate effect occurring. Ex: ach binds to curare and leads to muscle contraction: curare (acts as antagonist = paralysis) also binds to the same receptor and antagonizes. Ach as the endogenous ligand and blocks its effect. Same ligand can get very different biological effects depending on the tissue that the receptors is expressed on. If this becomes too prolonged, it can lead to an analgesic effect.
