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Questions and Answers
What observation did Sydney Ringer make about calcium's role in cardiac function?
What observation did Sydney Ringer make about calcium's role in cardiac function?
Which of the following proteins is associated with modulating GPCR signaling?
Which of the following proteins is associated with modulating GPCR signaling?
What happens to Ca2+ levels in the cytoplasm when a specific signaling event occurs?
What happens to Ca2+ levels in the cytoplasm when a specific signaling event occurs?
What is the primary function of Calmodulin in calcium signaling?
What is the primary function of Calmodulin in calcium signaling?
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Which channels are primarily involved in maintaining Ca2+ homeostasis within the cell?
Which channels are primarily involved in maintaining Ca2+ homeostasis within the cell?
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What is the primary role of GRKs in relation to GPCRs?
What is the primary role of GRKs in relation to GPCRs?
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Which of the following is an example of a GRK?
Which of the following is an example of a GRK?
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What does the phosphorylation of GPCRs by kinases such as PKC typically influence?
What does the phosphorylation of GPCRs by kinases such as PKC typically influence?
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What is the primary function of Calmodulin (CaM) after binding Ca2+?
What is the primary function of Calmodulin (CaM) after binding Ca2+?
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Which statement about the structural features of the β2-adrenergic receptor is true?
Which statement about the structural features of the β2-adrenergic receptor is true?
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What occurs to the structure of CaM when it binds to Ca2+?
What occurs to the structure of CaM when it binds to Ca2+?
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How can GRK activity be regulated?
How can GRK activity be regulated?
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What determines the specificity of GRKs for their substrates?
What determines the specificity of GRKs for their substrates?
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Which of the following proteins does Calmodulin NOT interact with?
Which of the following proteins does Calmodulin NOT interact with?
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How many EF-hand motifs are present in Calmodulin?
How many EF-hand motifs are present in Calmodulin?
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What happens to GPCRs following GRK-mediated phosphorylation?
What happens to GPCRs following GRK-mediated phosphorylation?
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What structural change occurs to CaM upon Ca2+ binding?
What structural change occurs to CaM upon Ca2+ binding?
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Which proteins are associated with GPCRs during endocytosis?
Which proteins are associated with GPCRs during endocytosis?
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What happens during the attachment of CaM to its target proteins?
What happens during the attachment of CaM to its target proteins?
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What does Ca2+-free Calmodulin resemble in its inactive form?
What does Ca2+-free Calmodulin resemble in its inactive form?
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Which is NOT one of the activation patterns caused by Calmodulin binding?
Which is NOT one of the activation patterns caused by Calmodulin binding?
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What role do RGS proteins play in G-protein signaling?
What role do RGS proteins play in G-protein signaling?
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Which of the following statements is true regarding CaM kinases?
Which of the following statements is true regarding CaM kinases?
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Which mechanism does RGS use to enhance G-protein signaling regulation?
Which mechanism does RGS use to enhance G-protein signaling regulation?
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What is a key function of CaM kinases I-IV?
What is a key function of CaM kinases I-IV?
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In the context of RGS, what molecule acts as a substrate?
In the context of RGS, what molecule acts as a substrate?
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How does RGS influence the reformation of the heterotrimer in G-protein complexes?
How does RGS influence the reformation of the heterotrimer in G-protein complexes?
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What effect does the activity of RGS have on G-proteins mediated by βγ subunits?
What effect does the activity of RGS have on G-proteins mediated by βγ subunits?
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Which example illustrates how a protein can remodel the active site to induce an active conformation?
Which example illustrates how a protein can remodel the active site to induce an active conformation?
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Study Notes
Calcium Signaling
- Calcium acts as a second messenger in signal transduction.
- Calcium homeostasis within cells is maintained by ryanodine receptors and IP3 receptors in the endoplasmic reticulum.
- Other components include calcium channels on the plasma membrane, Ca2+ ATPase on the plasma membrane, and sodium/calcium exchanger on the plasma membrane.
Proteins associated with GPCRs
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RGS (Regulators of G-protein signaling)
- Negatively regulate G-protein signaling by increasing the rate of GTP hydrolysis.
- RGS accelerates GTP hydrolysis, which shuts down the signaling system.
- RGS can also reduce the availability of G protein ßy subunits.
- RGS enhances the affinity of Go subunits for the By subunit after GTP hydrolysis.
- RGS increases the rate of hetero-trimer reformation.
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GRK (G-Receptor Kinases)
- Ser/Thr kinases that phosphorylate the agonist-occupied receptor.
- Leading to uncoupling of the G-protein from the receptor.
- Modulates receptor activity by different mechanisms.
- Seven types of GRKs, including rhodopsin kinase (GRK-1), β2-adrenergic receptor kinase (βARK-1 and 2).
Calcium as a Second Messenger
- At rest, calcium levels are low in the cytoplasm.
- Specific signals lead to a rapid increase in cytoplasmic calcium.
- An experiment in London (1883) demonstrated the importance of calcium for heart contraction.
Ca2+-Calmodulin
- Calmodulin (CaM) is a calcium-binding protein.
- Activation of CaM depends on the binding of four calcium ions.
- The binding of calcium to CaM changes its conformation, activating downstream targets.
- CaM activates target proteins by causing changes in conformation, such as exposing the catalytic site, changing the target conformation, assembling the target dimerization
- Several important targets for CaM include protein kinases, adenylyl cyclases, and phosphodiesterases.
Domains for Ca2+ Binding in Proteins
- Two domains for Ca2+ binding are EF-hand motifs and C2 domains.
- EF-hand motifs, found in Ca2+-binding proteins, convert ionic signals into biochemical responses.
- Binding of Ca2+ to EF-hand motifs induces a switch in Ca2+-binding proteins from an off state to an on state, allowing interaction with target proteins.
- C2 domains act as Ca2+-binding modules.
Calmodulin (CaM) Activation
- Ca2+-free Calmodulin is inactive, with a central helix shielded by terminal helices, preventing binding/interaction with targets.
- Ca2+ binding induces conformational changes in Calmodulin. exposing hydrophobic patches for target recognition and exposing the central alpha-helical segment, activating the protein.
- Calmodulin bound to target proteins, such as phosphorylase kinase, allows the central & helix to unwind and form a hinge.
- Ca2+/Calmodulin complex interacts with a binding site on the target protein, resulting in conformational change and activation.
CaM-Kinases
- CaM Kinases are target proteins for Calmodulin.
- They include phosphorylase kinase, myosin light chain kinase, and CaM kinases I-IV.
- Each CaM kinase interacts with CaM and converts the Ca2+ signal into a phosphorylation signal
Summary of activation patterns
- Attachment of CaM to its targets causes conformational changes characterized by 3 patterns. Conformational changes include: exposure of the catalytic site, changing the target conformation and assembling the structure of the target, inducing dimerization.
- There are at least three different activation patterns: the first relieves an auto-inhibition domain (AID); the second remodels the active site, causing an active conformation; and the third induces dimerization of K+ channels.
Ca2+/Calmodulin Targets
- Numerous targets exist including protein phosphorylation, protein dephosphorylation, Ca2+ transport, cyclic nucleotide metabolism (adenylyl cyclase, cyclic nucleotide phosphodiesterase)
- Other targets include nitric oxide formation, cytoskeleton components (MAP-2, Tau, fodrin, neuromodulin).
Calcium Generation Pathway: Signal Amplification
- This pathway demonstrates that GPCR and EGFR are capable of increasing calcium signaling in response to extracelluar signals
- This amplification can cascade and rapidly lead to the phosphorylation of a variety of proteins (CaMKII, PKC, MAPKs) and lead to downstream effects.
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Description
Explore the crucial roles of calcium as a second messenger in cellular signaling and understand the functionality of proteins associated with G-protein coupled receptors (GPCRs). This quiz will delve into mechanisms such as calcium homeostasis and the regulation of G-protein signaling by RGS and GRK. Test your knowledge on these essential cellular processes!
