G-Protein-Coupled Receptor Signaling Flashcards
How many G-Protein-Coupled receptors are present in the human genome, where do most of them localize, and what is their basic structure?
Over 1000 different GPcR in the human genome. Most localize in olfactory receptors, but they occur throughout the human body. They all have seven transmembrane domains with the N-teminus outside and C-terminus inside the cells.
What occur when an agonist binds to the GPcR?
An agonist will change the GPcR into an active conformation that induces the GPcR to interact with the G-protein inside the cell, which then causes the signal transduction within the cell
How do antagonists affect GPcR?
Most antagonists competitively bind to the active site of the GPcR and prevent it from interacting with agonists. Some bind allosterically, but the vast majority are competitive. 50% of all non-antibiotic prescription drugs target GPcR.
What is the reason behind the name G-protein and what is the basic structure of G-proteins?
G-protein interact with Guanine nucleotides (alpha unit) and are heterotrimeric proteins composed of alpha, beta, and gamma subunits. Alpha subunit interacts with the guanine nucleotide and the beta and gamma units are never found separated in cells.
What is the process of activation of a G-Protein?
Heterotrimeric G-protein is usually present in an inactive form, bound to GDP. An agonist binds to the GPcR, causing it to bind the G-protein and release the GDP from the alpha subunit. GTP is present in high concentrations, so GTP then binds to the open site on the alpha subunit, activating the G-protein and causing dissociation of the GTP-alpha subunit and the beta/gamma subunit. Active GTP-alpha is the signal transducer in the pathway, and is a GTPase that eventually hydrolyses GTP to GDP and inactivates the alpha subunit, favoring rebinding to the beta/gamma subunit.
How are G-Proteins involved in the Vibrio cholerae pathology?
The cholera toxin locks the G-alpha(s) subunit in the active state, constitutively activating Adenylyl cyclase to produce cAMP which then activates the CFTR Cl- channel. The G-alpha subunit is incapable of switching itself off under the influence of the cholera toxin.
How are G-Proteins involved in the Bordella Pertussis pathology?
The pertussis toxin affects the G-alpha(i/o) subunit and locks it in an inactive state by preventing receptor coupling.
How are GPcR involved in neuron signaling?
All sympathetic (adrenergic) and parasympathetic (muscarinic cholinergic) neuron signals target GPcRs. Adrenergic signals (Norepinephrine/epinephrine) target alpha and beta AR receptors, which then link to specific G-proteins. Muscarinic cholinergic signals (acetylcholine) target m2 or m3 AchR receptors, which then link to G-Proteins as well.
How do beta-Adrenergic Receptors (b-AR) respond to stimulation and affect cAMP production in the heart?
Nor-epinephrine or epinephrine (adrenergic agonists) bind to the beta-AR GPcR, triggering the activation of G-alpha(s) which activates Adenylyl cyclase (a transmembrane protein) to produce cAMP, which binds to and activates PKA affecting Ca2+ channel activity in the heart cells.
What effect do beta-blockers have on heart rate and blood pressure?
Beta-blockers are beta-AR antagonists and block adrenergic signals from triggering the G-alpha(s) pathway. This lowers the heart rate and blood pressure.
How do alpha-Adrenergic Receptors (a-AR) respond to stimulation and affect peripheral vasoconstriction?
NE, Epi, or Phenylephrine bind to alpha-AR receptors and activate G-alpha(q) which activates IP3, and DAG -> PKC, which increase Ca2+ concentrations in the muscle cells, causing contraction and vasoconstriction.
What effect do alpha-blockers have on blood pressure?
Alpha-blockers are alpha-AR antagonists and block andrenergic signals from triggering the G-alpha(q) pathway. This lowers blood pressure through vasodilation.
How do parasympathetic signals counteract sympathetic signals?
M2- Muscarinic cholinergic receptors (m2 AchR) bind Acetylcholine or Muscarine, activating G-alpha(i) which competes with G-alpha(s) to inactivate Adenylyl cyclases and limit the creation of cAMP in the cell. cAMP must still be degraded by PDEs (like cGMP is degraded by PDE5). The gamma/beta subunit is also activated and triggers the opening on GIRK K+ channels, hyper-polarizing the cell and making VGCa channels less likely to open, thus slowing the heart rate.
What effect would an m2 antagonist like atropine have on heart rate?
It would prevent the binding of acetylcholine or muscarine to the m2 AchR and increase heart rate.
What effect does PKA have in cardiac muscle? In smooth muscle?
In cardiac muscle, PKA causes contraction due to its effect on intracellular Ca2+.
In smooth muscle, PKA inhibits contraction via other pathways.
While these effects are opposite, they result in improving “fight or flight” responses by elevating heart rate, blood pressure, and increasing oxygen flow.
