membrane bound receptors Flashcards
Whats a receptor
A protein or group of proteins, usually embedded in the cell membrane, that allows the cell to collect information about its surroundings
Whats a Ligand
A chemical messenger (can be a small molecule or peptide) that binds and stabilizes a conformation of the receptor…neurotransmitter or Hormone, endogenous substances
whats a conformational change
change in the shape of a receptor that induces some downstream signal transduction.
What regulates receptor function
Regulated by molecules supplied by the body
Fyi
Drugs can only mimic or block the body’s own regulatory molecules they will not give a cell new function
whats an agonist
the drug combines with a receptor to stimulate target organ
Ligand that binds to a receptor and activates it
Stabilize active conformation
whats an antagonist
the drug combines with the receptor, but interferes with a naturally occurring agonist or an agonist drug.
Ligand that bind and disallows the molecules from initiating a repsonse
Interfere with agonist binding. The normal conformation fluctuations continue as if nothing was there
what are Pore blockers
Physically obstructs the channel (ion channels)
Partial agonist
weakly stabilize the
active state (e.g. ~50%) or
stabilize partially active state
What are inverse agonist
stabilize the inactive state reversing baseline/constitutive receptor activity
Stabilizes the inactive form …so u only have inactive form.
xxxInverse agonist actually stabilize the inactive form of the receptor and prevent any endogenous activity…mayb was active a little bit.
A true antagonist, will not knock out little endogenous activity…
Properties of receptors Are?
Active
Partially active
Inactive
Drugs can activate or inactivate receptors by stabilizing a pharmacologically significant conformation by binding:
to the same site as the endogenous compound (orthosteric site)
binding to an alternative site (allosteric site)
What’s the effect of a competitive antagonist on an Agonist
Effect of a competitive antagonist on the dose-response curve of an agonist.
Note that the maximal response achievable with the agonist is not reduced. Competitive
antagonists simply increase the amount of agonist required to produce any given intensity of
response.
What’s the effect of a noncompetitive Antagonist on an Agonist
Effect of a non-competitive antagonist on the dose-response curve of an agonist.
Note that noncompetitive antagonists decrease the maximal response achievable with an agonist.
What are the different types of receptors
Ligand-gated ion channels…nicotinic receptors
G-protein coupled receptors….7 transmembrane receptors span the membrane 7 times…composed of:receptor/g protein/effector…taste
Kinase-linked receptors…intracellular and extracellular domain
Nuclear receptors. Not cell membrane-bound…located in the cytoplasm…so it’s lipophilic
Ligand Gated characteristics ARe?
Location: Membrane Effector: ion Coupling: Direct This is a fast transmitting channel Composed of several subunits arranged around a central ion pore Agonist binding opens pore
Nicotinic, Ach,Gaba A receptor
Excitatory Vs Inhibitory response
Resting membrane potential: Inside of the cell has an overall negative charge of ~-70 mV
Excitatory: means that the inside of the cell’s charge approaches 0 mV
Generally by letting positive ions into the cell
Inhibitory: means that the inside of the cell’s charge becomes more negative
Generally by letting negative ions (mainly chloride) into of the cell
Gaba receptors influence chloride conduction thereby inhibitory
Potassium also can leave cell and making it also negative
What are the Major family of the Ligand-gated ion chanel
Cys-loop receptors: nicotinic acetylcholine receptor, glycine receptors, 5HT-3 receptor, etc. only excitatory present here
Ionotropic Glutamate Receptors: AMPA receptor, NMDA receptor, kainate receptor
components of Cys-Loop receptors
Named for the loop formed by the disulfide bond between two cysteines near the N-terminus
Made of five subunits arranged around a central pore
Five types of subunits: α, β, γ, δ, ε
Excitatory: Nicotinic acetylcholine receptors
how does gating occur with Cysa-loop receptors
The second transmembrane domain of the α subunit generally obstructs the ion pore
Agonist binding changes the conformation, moving the obstruction and allowing ions to flow through
the two Ach molecules are the Agonist and both need to bind.
Types of Cys-loop receptors are
Nicotinic acetylcholine receptors: Nicotine, Varenicline (Chantix)
GABAA receptors: Ambien (zolpidem)Barbituates, benzodiazepines, alcohol
Characteristics of Nicotinic acetylcholine receptors
Exist at the neuromuscular junction (NMJ) and in the CNS
NMJ nAChR contains a, β, δ, and γ subunits
Neuronal nAChRs contain only a and β subunits
Excitatory
Pass Na+, K+, and some Ca++ ions
Composed of five subunits
In the brain, nAChRs upregulate in response to chronic nicotine (like smoking)
2 ach molecules bind to open the nicotine receptors
Nicotine receptors…when u are chronically exposed there is an upregulation to receptors. This is the reason it is so difficult to stop smoking when u start
Nachr HAs 3 activation states namely?
Desensitized, closed and open
Ionotropic Glutamate receptors compose of
AMPA receptors, NMDA receptors, and Kainate receptors
Excitatory
Pass Na+ and K+ ions
NMDA receptors can also pass Ca++ ions
Composed of four subunits
Each subunit has four transmembrane domains
Second TM domain forms the ion pore
Each subunit has a binding site-not all binding sites are for glutamate
NMDA receptor: two binding sites for glutamate, two binding sites for glycine
All four binding sites must be occupied for the channel to open
Explain the process of long term potentiation
Long Term Potentiation (LTP): the more often a neuron fires, the “stronger” the synapse gets
Implicated in learning and memory
At resting membrane potential, NMDA receptors are blocked by Mg++
Magnesium block is voltage-dependent
Depolarization of neuron relieves the block, allows NMDAR to open
NMDARs pass Ca++, which activates CaMKII(calmodulin kinase II), which leads to AMPARs inserted into the synapse
More AMPARs = stronger synapse
Gprotein coupled receptors characteristics
Location: Membrane
Effector: Chanel or enzyme
coupling:G-protein or Arrestin
e.gsMuscarinic acetylcholine receptors, Adrenoceptors.
Slower signaling than ligand-gated ion channels
Rely on second messengers for signaling
~3% of our genome dedicated to GPCR coding
Target for more than half of current pharmaceuticals
3main classes of Gprotein receptors
Class A: adrenergic receptors, muscarinic acetylcholine receptors
Class B: Parathyroid Hormone receptor
Class C: metabotropic glutamate receptors, GABAB receptors
Ga subunits for G protein are ?
Gαs activation of adenylyl cyclase and increase in cAMP
Gαi inhibition of adenylyl cyclase and decrease in cAMP
Gαq activation of phospholipase C, phosphoinositol hydrolysis, increase in IP3 and DAG, and release of Ca2+ from intracellular stores
What are the target enzymes for Gprotein
Guanylate cyclase
Adenylate Cyclase
Phospholipase C
Gportein Effectors are:
Enzymes and transport proteins,Contractile proteins,Ion channels
Explain GPCR Desensitization
If a ligand is bound onto a GPCR for a prolonged period of time, β-arrestin binds to the receptor, thus tagging it for internalization
Contributes to drug tolerance
The GPCR-β-arrestin complex can act as a protein scaffold inside the cell
Independent of G protein signaling
