L1- Molecular and Cellular Aspects of Drug Action Flashcards
What are the four classes of receptors presented in the lecture?
- Ligand-Gated Ion Channels (Ionotropic Receptors)
* hyperpolarization / depolarization - G-Protein coupled receptors (Metabotropic)
* change in excitability, second messengers - Kinase-linked receptors
* protein phosphorylation; gene transcription; protein synthesis - Nuclear Receptors
* gene transcription; protein synthesis
What is an example of a Ligand-Gated Ion Channels/Ionotropic Receptor?
Nicotrinic Acetylocholine Receptor
What is an example of a G Protein-Coupled Receptor?
Adenylyl Cyclase
Alpha2 adrenergic receptor
Beta-adrenergic receptors
What is an example of a Kinase-linked Receptor?
Receptor Tyrosine Kinases (RTK): Receptors for many growth factors; phosphorylates tyrosine residues)
Cytokine receptors
Serine/threonine Kinases
Guanylyl cyclase-linked receptors
What is an example of a Nuclear receptor?
Estrogen receptors
What is the timescale on which each class functions?
- Ligand-Gated Ion Channels (Ionotropic Receptors): MILISECONDS
- G-Protein coupled receptors (Metabotropic): SECONDS
- Kinase-linked receptors: HOURS
- Nuclear Receptors: HOURS
What two scientists near the beginning of the 20th century put forward receptor theory?
-
Paul Erlich: Proposed anti-bodies bound to side chains on their antigens. (Side chain renamed RECEPTORS)
* COINED LOCK-AND-KEY -
John Langley: Applied immunology to neuroscience and saw interaction with drugs with “Receptive substances.”
* Demonstrated nicotine causes contractions
Agonist
A molecule that binds to the receptor and “causes” an effect (Activates)
Antagonist
A molecule that binds to the receptor and “prevents” an effect
Orthosteric
The binding site for ligands (Agonist site/ACTIVE SITE)
Allosteric
The place on an enzyme where a molecule that is not a substrate may bind, thus changing the shape of the enzyme and influencing its ability to be active.
PAM
Positive Allosteric Modulator
- induce an amplification of the effect of the primary ligand
NAM
negative allosteric modulator
- reduces the effect of the primary ligand
Why is the control of calcium levels in the cell so important?
Calcium is an excitatory ion, where increased levels can release neurotransmitters and activate of enzymes. BUT, too much calcium for too long is toxic.
- Activated proteolytic enzymes/mechanisms can kill the cell.
- Ca2+ increases contractility in smooth muscle so too much Ca 2+ → TETANUS
What systems does an increase in Ca++ affect?
- Musculoskeletal (muscle contraction!!)
- Cardiac
What are normal Ca++ in and out?
At rest, there is more Ca2+ outside the cell (2 mmol/l) than inside (0.1 micro-mol/l)
What mechanisms can change [Ca++] in?
Activation of GPCR
- IP3 liberates Ca2+ from inside endoplasmic reticulum
Ligand-gated cation channel
- Agonist (ATP or Glutamate) bind to membrane receptors and allow Ca+2 to rush into the cell
Voltage-gated calcium channel
- Depolarization; Ca2+ rush in
Na+-Ca2+ exchange
- Ca2+ rushes out when Na+ flows down its concentration gradient.
Store-operated calcium channels (SOCs) ???
- Ex: Mitochondria stores calcium and only releases Ca2+ under pathological conditions.
- Evidence of activation by the second messenger nicotinic acid dinucleotide phosphate
Which ions, flowing through channels, are excitatory?
Na+ and Ca2+
(They depolarize)
Which ions, flowing through channels, are inhibitory?
K+ and Cl-
(They hyperpolarize)
What is one set of enzymes that control cellular proliferation?
Cyclin-Dependent Kinase (CDKS)
Why is the set of enzymes that control cellular proliferation important?
Cell proliferation is involved in
- growth
- healing
- repair
- hypertrophy
- hyperplasia
- development of tumors.
Thus, inhibiting cyclin-dependent kinase will inhibit over-proliferation that is responsible for the development of tumors
*Acetylcholine is the endogenous agonist for the nicotinic acetylcholine receptor. It binds to:
a. An allosteric site and is a PAM
b. An allosteric site and is a NAM
c. The orthosteric site
d. The orthorhombic site
e. None of the above
C. The orthosteric site
*Na+ and K+ are ions that flow through ion channels. When Na+ or K+ channels open and the ion flows:
a. They both excite cells (depolarize)
b. They both inhibit cells (hyperpolarize)
c. Na+ depolarizes while K+ hyperpolarizes
d. K+ depolarizes while Na+ hyperpolarizes
e. None of the above.
C. Na+ depolarizes while K+ hyperpolarizes
*The enzyme adenyl cyclase converts ATP into cyclic AMP. The most common way to stimulate this enzyme is via:
a. Ligand-gated channels
b. G-Protein Coupled Receptors
c. Kinase-linked Receptors
d. Nuclear Receptors
e. None of the above.
b. G-Protein Coupled Receptors
*What are the normal resting concentrations of calcium?
a. 0.1 µM out and 2 mM in
b. 0.1 µM in and 2 mM out
c. 2 mM in adn 145 mM out
d. 5mM in and 125 mM out
e. 145 mM in and 12mM out
b. 0.1 µM in and 2 mM out
Which superfamily of receptors is NOT typically membrane-bound?
A. GPCR
B. Ligand Activated transcription factors
C. Kinase-linked
D. None of the Above
B. Ligand Activated transcription factors
(nuclear-bound receptors)
Which receptor superfamily normally signals on the sub-second time scale?
A. Ion channels
B. Kinase-linked
C. Ligand-activated transcription factors
D. None of the above
A. Ion channels
Which ions, flowing through open channels, excite (depolarize) a cell? Choose all that apply?
A. Potassium
B. Sodium
C. Chloride
D. Calcium
E. Protons
B. Sodium
D. Calcium
E. Protons
Occupation is governed by affinity which is the tendency of a drug to activate the receptor once bound.
a. True
b. False
B. FALSE
A nicotinic acetylcholine receptor is an example of what type of receptor?
a. G-protein coupled receptor
b. Nuclear receptor
c. Ligand-gated ion channel
d. Kinase-linked receptor
e. Symporter
c. Ligand-gated ion channel
The ability of ion channels to transition between closed (resting) state and an open (inactivation) state is significant because:
a. This prevents overexcitation of the cell
b. This is necessary for GABA to bind to the GABA receptors
c. Drugs can target this system and prevent inactivation or activation.
d. The transition modulates the abilities of various drugs
e. The transition is an example of a conformational change which is a hallmark of drug
targets.
c. Drugs can target this system and prevent inactivation or activation.
High concentrations of Ca 2+ is toxic because
a. High concentrations can interfere with VGCC proteins and cause hypertension
b. High concentrations can limit the amount of calcium sequestered in the endoplasmic reticulum and mitochondria
c. High concentrations of calcium prevent the release of ATP
d. High concentrations can activate calcium-dependent proteases and initiate apoptosis
D. High concentrations can activate calcium-dependent proteases and initiate apoptosis
The movement of __, __, and __
ions across the cell membrane excite (depolarize) the cell.
Excitatory: Na+, Ca+2, H+ (protons)
- The movement of Na+, Ca2+, and H+*
- ions across the cell membrane excite (depolarize) the cell.*
The movement of __ and __ ions
across the cell inhibit (hyperpolarize) the cell.
Inhibitory: K+, Cl
- The movement of K+ and Cl ions*
- across the cell inhibit (hyperpolarize) the cell.*
