Drug Targets: Receptors and Channels

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Questions and Answers

Which of the following statements about the sweet taste receptor is true?

It is a heterodimer composed of two short GPCR monomers.

It is a homodimer composed of two short GPCR monomers.

It is a homodimer composed of two full-length GPCR monomers.

It is a heterodimer composed of two full-length GPCR monomers. (correct)

What is the role of the long amino terminus in the sweet taste receptor?

It forms a "venus flytrap" binding pocket for the tastant. (correct)

It releases calcium from intracellular stores.

It activates the G protein.

It hydrolyzes phospholipids in the plasma membrane.

What happens when GTP is bound to a G protein?

The G protein hydrolyzes phospholipids.

The G protein releases calcium from intracellular stores.

The G protein is activated. (correct)

The G protein is inactivated.

What is the role of phospholipase C (PLC) in the signal transduction cascade?

It hydrolyzes phospholipids in the plasma membrane. (B) Signup and view all the answers

What is the role of IP3 in the signal transduction cascade?

It releases calcium from intracellular stores. (D) Signup and view all the answers

What is the effect of microinjection of IP3 in neuroepithelioma cells?

Increased intracellular calcium release (A) Signup and view all the answers

What is the role of β-arrestins in the down-regulation of receptors?

They bind to the phosphorylated C-terminus of the GPCR and recruit clathrin. (D) Signup and view all the answers

What is the function of Adenylyl Cyclase?

It converts ATP to cAMP. (C) Signup and view all the answers

What is the effect of caffeine on Adenylyl Cyclase?

It stimulates Adenylyl Cyclase activity. (C) Signup and view all the answers

Which of the following is NOT a mechanism involved in the down-regulation of receptors?

Activation of G proteins (A) Signup and view all the answers

Which of the following is NOT a specific example of an agonist for nuclear receptors?

Insulin (B) Signup and view all the answers

What is the primary function of nuclear receptors?

To regulate the expression of specific genes (A) Signup and view all the answers

Which of the following is a characteristic of Class II nuclear receptors?

They are already located in the nucleus bound to DNA in their inactive state (A) Signup and view all the answers

Which of the following is NOT a component of the transcription initiation complex assembled by nuclear receptors?

Corepressor protein (C) Signup and view all the answers

What is the role of Heat Shock Proteins (HSPs) in the activation of Class I nuclear receptors?

HSPs act as chaperones, keeping the receptor in an inactive state in the cytosol. (C) Signup and view all the answers

What is the primary mechanism by which prolonged exposure to an antagonist can lead to sensitization?

Antagonist upregulates the expression of the receptor gene (D) Signup and view all the answers

What is the role of the Hormone Response Element (HRE)?

HRE is a sequence on DNA that binds to the ligand-receptor complex. (C) Signup and view all the answers

Which of the following is a common characteristic of both Class I and Class II nuclear receptors?

They are involved in the regulation of gene expression. (C) Signup and view all the answers

Which of the following is an example of a Class II nuclear receptor?

Thyroid hormone receptor (D) Signup and view all the answers

What is a possible outcome of upregulation of receptors due to prolonged exposure to an antagonist?

Increased sensitivity to the agonist (D) Signup and view all the answers

What is the approximate molecular weight of Class A GPCRs?

45 kDa (D) Signup and view all the answers

Where does ligand binding occur in Class A GPCRs?

In a lipophilic pocket within the 7 TM region (B) Signup and view all the answers

Which of the following is a true statement about Class B GPCRs?

They form functional heterodimers. (C) Signup and view all the answers

What is the mechanism of activation of PAR-1 (Protease Activated Receptor)?

Cleavage of the amino terminus by a protease, resulting in a tethered ligand (C) Signup and view all the answers

Which of the following is NOT a class of drug targets?

Hormones (C) Signup and view all the answers

Which of the following is a common characteristic of both GPCRs and ion channels?

They both are activated by the binding of small molecules. (B) Signup and view all the answers

Which of the following is a characteristic of Class C GPCRs?

They have a large amino terminus involved in ligand binding. (C) Signup and view all the answers

Which of the following drug targets are NOT directly involved in the transport of molecules across cell membrane?

Enzymes (C) Signup and view all the answers

Study Notes

Drug Targets

Cell surface receptors
- G protein-coupled receptors (GPCRs)
- Ion channels
  - Voltage-gated channels
  - Ligand-gated channels
- Enzyme-linked receptors
  - Enzymes
  - Transporters
Nuclear receptors

Targets of Current Marketed Drugs

GPCRs (7TM1) account for 33% of small molecule drugs that target major families
Ion channels represent 18%
Kinases 16%
Nuclear receptors 10%
Other 3%
Enzymes and transporters account for 30% of small molecule drugs that target major families

Ion Channels and GPCRs

Ion channels
- Neurotransmitter binds directly to ion channel protein
- Channel opens immediately
- Ions flow across membrane for a brief time
G protein-coupled receptors (GPCRs)
- Neurotransmitter binds G protein-coupled receptors
- G protein becomes activated
- G protein subunit moves to adjacent ion channel, causing short delay
- The activated subunit also triggers second messenger systems (which are not shown in the diagram)
- Channel opens, and ions flow across membrane for longer period

Class A Example: β-adrenergic Receptor

Helices of membrane-spanning domains form binding pocket for norepinephrine
Keeping molecule in place through molecular interactions

Major Classes of GPCRs

Class A
- Most numerous and diverse
- ~45 kDa
- Relatively short amino terminus
- Small molecule binding site in lipophilic pocket
- Binding within the 7 TM region
Class B
- Longer amino terminus, can sometimes bind ligands
- Ligands predominantly bind to extracellular loops
- Typical ligands are peptides and small proteins
Class C
- ~80 kDa
- Very large amino terminus
- Forms functional heterodimers
- Agonists bind mostly in amino terminus
- Binding sites can occur all over the receptor molecule

Class B Example: PAR-1 (Protease Activated Receptor)

N-terminus of PAR-1 contains protease cleavage site
Cleavage by thrombin results in a new N-terminus
Sequence SFLLRN acts as tethered ligand
Binds intramolecularly to heptahelical body of receptor
Effects transmembrane signaling and G protein activation

Class C Example: Sweet and Umami Tastant Receptors

Sweet taste receptor is heterodimer composed of two full-length GPCR monomers
Long amino terminus forms "venus flytrap" binding pocket

Guanosine Tri- and Di-phosphates

Nucleotides in G protein activation cycle
- GTP is 3 phosphates
- GDP has 2 phosphates

GPCRs Can Initiate a Signal Transduction Cascade

G protein must be activated, GTP to GDP will inactivate nearby G proteins, but when attached to GTP it is activated.
Ligand binds to receptor
G protein releases GDP and binds GTP, activating G protein
Subunits separate
G protein subunits activate or inhibit target proteins
Ga subunit hydrolyzes its bound GTP to GDP and becomes inactive
Subunits recombine to form inactive G protein

Phospholipase C in an Enzyme

PLC takes pieces from phospholipid searching for PIP2 to cleave A phosphate group, creating IP3 and DAG
IP3 is a messenger for cell which is on surface of ER called IP3R, opening up the channel, CA2+ will exit into cytoplasm

IP3 Causes Release of Calcium

IP3 binds IP3-receptor channels
Calcium is released from ER and SR

IP3 Microinjection

Microinjection of IP3 in neuroepithelioma cells evokes intracellular release of calcium and subsequent paracrine calcium signaling

Adenylyl Cyclase

Adenylyl cyclase is an enzyme in the plasma membrane that converts cytosolic ATP to cAMP
Takes ATP
Creates cAMP
PDE (phosphodiesterase) converts cAMP to AMP
Inhibitors: Caffeine, Sildenafil, Theophylline

Down-regulation of Receptors

Following agonist binding, GRKs are activated
Phosphorylate agonist-bound receptor
Phosphorylated C-terminus recruits β-arrestins
β-arrestins bind and polymerize clathrin proteins, forming cages that stabilize the receptor complex

Up-regulation of Receptors

Prolonged exposure to antagonist
Chronically low levels of intrinsic neurotransmitter or hormone agonist
Pathological factors impacting gene regulation and protein expression

Nuclear Receptors

Nuclear receptors are transcription factors
- Directly bind to DNA to regulate specific gene expression
General structure
- Ligand binding domain
- DNA binding domain
Examples of Agonists for Nuclear receptors
- Steroid hormones
  - Estradiol
  - Testosterone
  - Cortisol
  - Aldosterone
- Retinoic acid (metabolite of vitamin A)
- Calcitriol (active form of vitamin D)
- Triiodothyronine (thyroid hormone T3)

Nuclear Receptor Mechanism of Action - Class I

Receptor located in the cytosol bound to Heat Shock Protein (HSP)
Ligand diffuses across membrane, binds to receptor
Ligand-Receptor (LR) complex dissociates from HSP
LR complex translocates to nucleus
LR complex binds Hormone Response Element (HRE) sequence on DNA
LR complex recruits additional proteins to form a transcription initiation complex
Transcription of DNA to RNA

Nuclear Receptor Mechanism of Action - Class II

Unoccupied receptor already located in the nucleus bound to DNA
Unoccupied receptor is bound to a corepressor protein
Ligand binding to thyroid hormone receptor (TR) causes dissociation of corepressor and recruitment of coactivator protein, polymerase

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Description

This quiz explores the various drug targets, including cell surface receptors like GPCRs and ion channels. It assesses your understanding of the significance of these targets in current marketed drugs and their mechanisms of action. Test your knowledge on how these components play a crucial role in pharmacology.