L7 Pharmacology: G Proteins as Drug Targets

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Questions and Answers

What occurs at rest in the G protein cycle regarding the receptor and G protein?

At rest, the receptor and G protein separate.

Describe the role of ligand binding in the activation of a GPCR.

Ligand binding activates the receptor, allowing it to link with the G protein at the C terminus.

Explain the function of the RGS protein in the G protein cycle.

RGS acts as a regulator of G-protein signaling, enhancing GTPase activity of the alpha subunit.

What happens to the alpha subunit during the activation step of the G protein cycle?

The alpha subunit binds GTP and becomes activated. Signup and view all the answers

How does GTPase activity influence the G protein cycle?

GTPase activity of the alpha subunit converts GTP to GDP, leading to the reassociation with the beta-gamma subunit. Signup and view all the answers

What is the significance of the G protein cycle being 'nothing used up'?

It signifies that the cycle can repeatedly activate and deactivate without depleting cellular resources. Signup and view all the answers

What are the primary effects of the Gq/G11 family of G-proteins on intracellular signaling?

Gq/G11 increases intracellular calcium and stimulates the production of second messengers such as IP3, DAG, and PIP2. Signup and view all the answers

Describe the process of G-protein activation once a ligand binds to a GPCR.

Upon ligand binding to the GPCR, the G protein associates with the receptor, GDP is replaced by GTP on the alpha subunit, activating it and leading to dissociation from the beta-gamma complex. Signup and view all the answers

Identify the four subfamilies of G-proteins and their corresponding main roles.

The four subfamilies are Gs (stimulates adenylyl cyclase), Gi (inhibits adenylyl cyclase), Gq (activates phospholipase C), and G12/13 (activates Rho-GEF). Signup and view all the answers

In terms of second messengers, what specific molecules are produced by the action of Gq proteins?

Gq proteins alter the levels of IP3, DAG, and PIP2, which are vital for calcium signaling and cellular responses. Signup and view all the answers

Explain the role of GTPase activity in the deactivation of a G-protein.

GTPase activity hydrolyzes GTP to GDP, converting the active G protein back to its inactive state, allowing the reassociation of the alpha subunit with the beta-gamma complex. Signup and view all the answers

What distinguishes Gi from Gs in terms of effector interaction and signaling outcome?

Gi inhibits adenylyl cyclase, leading to a decrease in cAMP levels, whereas Gs stimulates adenylyl cyclase, resulting in increased cAMP levels. Signup and view all the answers

What are the potential effects of beta-gamma subunits in cellular signaling?

Beta-gamma subunits can activate kinases, inhibit calcium channels, activate potassium channels, and inhibit alpha subunit signaling. Signup and view all the answers

Identify two human diseases linked to toxins that affect G-proteins.

Cholera and whooping cough are caused by toxins acting on G-proteins. Signup and view all the answers

Define ADP ribosylation and its significance in the context of G-proteins.

ADP ribosylation is the addition of ADP molecules to G-proteins, altering their structure and function. Signup and view all the answers

Provide an example of a therapeutic drug that targets G-proteins and describe its mechanism.

YM-254890 inhibits Gq proteins, affecting signaling pathways associated with these proteins. Signup and view all the answers

How do beta-gamma subunits influence calcium channels and neurotransmitter release?

Beta-gamma subunits inhibit calcium channels, which reduces neurotransmitter release. Signup and view all the answers

What role do kinases play in the effects mediated by beta-gamma subunits?

Kinases activated by beta-gamma subunits can phosphorylate various proteins, modulating cellular activities. Signup and view all the answers

What are the key components of heterotrimeric G-proteins?

Heterotrimeric G-proteins consist of three subunits: alpha (α), beta (β), and gamma (γ). The alpha subunit binds GDP or GTP, while beta and gamma remain associated. Signup and view all the answers

Describe the process of G-protein activation after a ligand binds to a GPCR.

Upon ligand binding to a GPCR, the receptor undergoes a conformational change that facilitates the exchange of GDP for GTP on the alpha subunit, activating the G-protein. This leads to the separation of the alpha subunit from the beta and gamma subunits. Signup and view all the answers

What is GTPase activity, and why is it important in the functioning of G-proteins?

GTPase activity refers to the hydrolysis of GTP to GDP and inorganic phosphate (PO4), which deactivates the G-protein. This is important for resetting the signaling pathway and ensuring that the cellular response is temporally regulated. Signup and view all the answers

Identify one G-protein subtype and its associated GPCR.

The Gs protein subtype is associated with beta-adrenergic receptors. Stimulation of these receptors activates adenylate cyclase, increasing cAMP levels. Signup and view all the answers

How do beta and gamma subunits interact with cellular effectors once the G-protein is activated?

Once activated, the beta and gamma subunits can directly interact with various effector proteins, such as ion channels or enzymes, to propagate the signal within the cell. These interactions can modulate cellular activities like ion flow or enzyme activity. Signup and view all the answers

Explain the significance of the seven transmembrane domains in GPCRs regarding G-protein activation.

The seven transmembrane domains of GPCRs facilitate the binding of ligands and initiate conformational changes necessary for G-protein activation. This structural feature is critical for transmitting signals across the plasma membrane. Signup and view all the answers

Discuss the role of G-proteins in second messenger systems.

G-proteins activate various second messenger systems, such as cAMP or phosphoinositides, after being activated by GPCRs. These second messengers relay and amplify signals within the cell, leading to various physiological responses. Signup and view all the answers

What is the significance of the ability of more than one G-protein to be activated by a single receptor?

The ability for a single receptor to activate multiple G-protein types allows for diverse signaling pathways and responses within the cell. This multiplicity enhances the versatility and complexity of cellular signaling. Signup and view all the answers

What are the effects produced by βγ subunits in G-protein signaling?

βγ subunits activate kinases, inhibit calcium channels, activate potassium channels, and mop up alpha subunits to inhibit signaling. Signup and view all the answers

What is the primary effect of cholera toxin on G-proteins?

Cholera toxin activates Gs and Gt, leading to constant activation of G-protein signaling. Signup and view all the answers

How does pertussis toxin affect G-protein signaling?

Pertussis toxin inhibits Gi and Go, preventing G-protein binding to receptors. Signup and view all the answers

What role does ADP ribosylation play in the function of G-proteins?

ADP ribosylation alters the function of G-proteins, which can activate or inhibit their signaling activity. Signup and view all the answers

What is the consequence of ADP ribosylation at Arg 201 in Gs G-protein?

ADP ribosylation at Arg 201 prevents GTPase activity, leading to prolonged G-protein activation. Signup and view all the answers

What happens when ADP ribosylation occurs at Cys351 in Gi or Go G-proteins?

ADP ribosylation at Cys351 inhibits receptor coupling of Gi and Go G-proteins. Signup and view all the answers

Describe the action of mastoparan on G-proteins.

Mastoparan activates Gi G-proteins, influencing their signalling pathways. Signup and view all the answers

What G-proteins does Pasteurella multocida toxin activate?

Pasteurella multocida toxin activates Gq, G11, G12, G13, and Gi G-proteins. Signup and view all the answers

Study Notes

G-Proteins as Drug Targets

Heteromeric G-proteins consist of three subunits: alpha (α), beta (β), and gamma (γ).
G-proteins can undergo a cycle of activation and deactivation by switching GDP for GTP.
GTPase activity of G-proteins converts GTP back to GDP, re-establishing the resting state.

G-Protein Activation

Receptors, when activated by ligand binding, interact with G-proteins at their C terminus.
Following receptor activation, the alpha subunit dissociates from the beta and gamma subunits.
G-protein activation allows the alpha subunit to bind GTP, leading it to interact with effectors.

G-Protein Subtypes and Signaling

Main subtypes: Gs, Gi, Gq, and G12/13.
Gs activates adenylyl cyclase, increasing cAMP levels.
Gi inhibits adenylyl cyclase, leading to reduced cAMP levels.
Gq activates phospholipase C, resulting in increased levels of IP3, DAG, and PIP2, which heighten intracellular calcium.

Beta and Gamma Subunits

Beta and gamma subunits remain associated and can activate various signaling pathways.
They activate kinases, inhibit certain calcium channels, and regulate potassium channels to modulate excitability.

Toxins Affecting G-Proteins

Cholera toxin (CTX): Activates Gs and Gt, causing excessive signaling.
Pertussis toxin (PTX): Inhibits Gi and Go, leading to disrupted signaling.
Mastoparan: Activates Gi from wasp venom, affecting signaling pathways.
Pasteurella multocida toxin (PMT): Activates multiple G-protein subtypes, including Gq and G12.

ADP Ribosylation

A modification where ADP is added to G-proteins, altering their function.
Cholera toxin results in constant activation of Gs, while pertussis toxin prevents G-protein receptor coupling.

Disease Associations

Pertussis toxin is associated with whooping cough due to its impact on G-protein signaling.
Toxins can cause disruptions in normal G-protein functions, leading to various health issues.

Therapeutic Applications

YM-254890 is a drug derived from chromobacterium that inhibits Gq proteins, showcasing potential therapeutic effects on G-protein pathways.

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Description

Explore the role of heteromeric G-proteins in pharmacology and their association with the GPCR family. This quiz covers crucial concepts related to drug design and development, focusing on G-proteins as potential drug targets. Enhance your understanding of their function and importance in the pharmacological landscape.