MOLECULAR PHARMACOLOGY: G Protein-Coupled Receptors

These flashcards cover key concepts, mechanisms, and terminology related to G Protein-Coupled Receptors (GPCRs), including their structure, function, and pharmacology as discussed in the lecture notes.

What class of GPCRs contains orthosteric ligand binding sites in the upper TMD and/or ECD depending on ligand size?

Class A GPCRs.

What type of ligands do Class B GPCRs recognize during binding?

Peptide ligands.

What are the key residues for orthosteric β2 adrenergic receptor ligand binding?

D113 and N312.

What is the role of proline in the structure of GPCRs?

Proline breaks α-helices, providing flexibility.

Which mechanism is common among almost all GPCR activations?

Outward movement of TM6.

What type of interactions stabilize Class A GPCR conformational changes?

Intramolecular bonds between TM3, TM6, and TM7.

What is biased signaling in the context of GPCRs?

Different system components stabilize different receptor conformations, leading to differential activation of effectors.

Which ligands reduce activity below basal levels due to constitutive activity?

Inverse agonists.

Which molecular structures are crucial for Class C GPCR activation?

Venus flytrap (VFT) modules.

What does the β2 adrenergic receptor primarily bind?

Endogenous monoamines such as adrenaline.

What do agonists typically form with multiple residues in TM5?

Hydrogen bonds.

What is the primary action of Class B GPCRs upon peptide hormone binding?

Large-scale changes in the TM core architecture.

What role do allosteric modulators play in GPCR activity?

They alter receptor conformation induced by an orthosteric ligand.

What kind of activity do neutral antagonists exhibit?

They can only reduce activity to basal levels.

What are the common conserved motifs in Class A GPCRs?

CWxP, PIF, DRY, NPxxY.

How does ligand binding initiate signaling in GPCRs?

Through allosteric interaction networks that relay signals from the ligand-binding pocket to intracellular partners.

What is the structural function of disulfide bridges in GPCRs?

They anchor the extracellular side of transmembrane segments.

How does the activation effect of Class B GPCRs differ from Class A GPCRs?

Class B GPCRs experience a unique outward movement of TM6 compared to Class A GPCRs.

Which method is used to measure pocket volume changes in β2AR?

Counting water molecules and measuring size in Å.

What key role does the Na+ pocket play in β2AR activation?

It collapses to initiate movement towards TM7 and TM6.

What leads to the breaking of the 'ionic lock' in Class A GPCRs?

Outward movement of TM6 during activation.

What characterizes the ligand-binding process in Class B GPCRs?

A two-step peptide binding process involving both ECD and TMD.

How do biased ligands affect GPCR function?

They stabilize receptor conformations that favor interactions with specific effectors.

Which structure provides a common interface among TM helices in Class C GPCRs?

The rotation of TM6 helices upon agonist binding.

What is the difference between biased and balanced signaling?

Biased signaling leads to differential activation of effectors based on receptor conformation.

What is the effect of hydrophobic interactions in β2AR agonist binding?

They stabilize and activate the receptor.

How do proline kinks facilitate GPCR activation?

They provide flexibility and enable movements at the cytoplasmic end of the receptor.

What occurs upon the binding of agonists to β2AR?

It opens the intracellular pocket significantly more than antagonist or inverse agonist binding.

What defines the structural basis of allosterism in GPCRs?

Binding of a ligand at a site other than the orthosteric site that influences receptor function.

What structural change occurs in Class C GPCRs upon agonist binding?

Conformational shift of the VFT module from an open to closed state.

How does adrenaline affect the β2 adrenergic receptor?

It rearranges hydrophobic interactions leading to activation.

What defines constitutive activity of GPCRs?

Basal activity present even without agonist binding.