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Questions and Answers
What is the function of VGCaCs?
What is the function of VGCaCs?
How do voltage-gated cation channels allow ions to pass through?
How do voltage-gated cation channels allow ions to pass through?
How do Ca2+ channels achieve ion selectivity?
How do Ca2+ channels achieve ion selectivity?
What is the function of nicotinic acetylcholine receptors?
What is the function of nicotinic acetylcholine receptors?
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What is the structure of voltage-gated cation channels?
What is the structure of voltage-gated cation channels?
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What happens when both Ca2+ binding sites are occupied in a Ca2+ channel?
What happens when both Ca2+ binding sites are occupied in a Ca2+ channel?
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How do K+ channels differ from Na+ and Ca2+ channels?
How do K+ channels differ from Na+ and Ca2+ channels?
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What happens in closed ion channels?
What happens in closed ion channels?
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What is the shape formed by the residues at the tip of TMD6 in closed channels?
What is the shape formed by the residues at the tip of TMD6 in closed channels?
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What is the net charge of the residues on TMD4 that form the voltage sensor?
What is the net charge of the residues on TMD4 that form the voltage sensor?
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What happens to the voltage sensor residues on TMD4 when the PM depolarizes?
What happens to the voltage sensor residues on TMD4 when the PM depolarizes?
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What is the role of the short cytosolic helix linking TMD4-5?
What is the role of the short cytosolic helix linking TMD4-5?
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What happens to the pore-lining helices when the channel opens?
What happens to the pore-lining helices when the channel opens?
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What is the outcome of phosphorylation of Akt2 by PDK1?
What is the outcome of phosphorylation of Akt2 by PDK1?
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What is the role of the SH2 domain of p85 adaptor subunit of PI3K?
What is the role of the SH2 domain of p85 adaptor subunit of PI3K?
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What is the outcome of mTORC2 recruitment in the fed state?
What is the outcome of mTORC2 recruitment in the fed state?
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What is the function of phosphor-tyrosine residues on the receptor?
What is the function of phosphor-tyrosine residues on the receptor?
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What is the outcome of insulin signalling pathway?
What is the outcome of insulin signalling pathway?
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What is the role of IRS1 in insulin signalling pathway?
What is the role of IRS1 in insulin signalling pathway?
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What is the role of the PTB domain in the insulin signalling pathway?
What is the role of the PTB domain in the insulin signalling pathway?
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What is the outcome of phosphorylation of PIP2 by PI3K?
What is the outcome of phosphorylation of PIP2 by PI3K?
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Which protein is recruited to the scaffold protein PIP3 by its PH domain?
Which protein is recruited to the scaffold protein PIP3 by its PH domain?
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What is the outcome of inhibition of glycogen synthase kinase?
What is the outcome of inhibition of glycogen synthase kinase?
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What is the outcome of the formation of Rab-GTP?
What is the outcome of the formation of Rab-GTP?
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What is the function of Maraviroc in relation to HIV?
What is the function of Maraviroc in relation to HIV?
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What is the result of loss of function mutations in the V2 receptor?
What is the result of loss of function mutations in the V2 receptor?
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What is the outcome of mutations in the TSH receptor?
What is the outcome of mutations in the TSH receptor?
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Which receptor is involved in the regulation of water reabsorption in the kidney?
Which receptor is involved in the regulation of water reabsorption in the kidney?
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What is the function of the CD4 receptor in relation to HIV?
What is the function of the CD4 receptor in relation to HIV?
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What is the role of active GPCRs?
What is the role of active GPCRs?
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Why do boys with a mutated α_s subunit of the Gs protein experience precocious puberty?
Why do boys with a mutated α_s subunit of the Gs protein experience precocious puberty?
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What is the role of RGS proteins in G-protein signaling?
What is the role of RGS proteins in G-protein signaling?
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What is the effect of upregulating RGS6 in alcoholic mice?
What is the effect of upregulating RGS6 in alcoholic mice?
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What is the potential therapeutic application of inhibiting RGS6?
What is the potential therapeutic application of inhibiting RGS6?
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What is the consequence of intrinsic GTPase activity in G-proteins?
What is the consequence of intrinsic GTPase activity in G-proteins?
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Study Notes
Ion Channels
- Ion channels open and close quickly, in less than 1 ms, and can allow several million ions to pass through.
- They mediate the fastest communication in the cell.
Regulation of Intracellular Activities
- Membrane potential changes are transduced as a messenger that enters the cell, typically calcium, through the opening of voltage-gated calcium channels (VGCaCs).
- VGNa/KCs are analogous to cables, while VGCaCs are analogous to the appliance, and VGICs are important therapeutic targets.
Nicotinic Acetylcholine Receptors
- Nicotinic acetylcholine receptors, found in muscle, respond to acetylcholine (ACh) released from pre-synaptic fibers.
- Drugs interacting with these receptors can relax muscle (during surgery) and treat myasthenia gravis (an autoimmune condition).
GABA/Glycine Receptors
- GABA/glycine receptors, which are chloride permeable, mediate most synaptic transmission in the CNS.
- Drugs targeted to these receptors are used to relieve anxiety and as general anesthetics.
Voltage-Gated Cation Channels
- Voltage-gated cation channels consist of 24 membrane spanning regions (4 × 6) arranged around a central pore.
- For Na+ and Ca2+ channels, the entire channel is comprised of a single protein chain.
- For K+ channels, four protein chains, each with six membrane-spanning domains, are required.
Ion Selectivity
- Ion selectivity arises from a narrow selectivity filter, where cations pass through single file, and surrounding amino acid residues interact.
- The selectivity filter of Ca2+ channels has two Ca2+ binding sites, which can bind Ca2+ selectively and tightly, allowing selectivity.
Channel Gating
- In closed channels, the residues at the tip of TMD6 come together to form a tepee shape, occluding the channel.
- The voltage sensor consists of four positively charged residues on TMD4, which move outwards in the plane of the membrane when the PM depolarizes.
- This movement pulls a short cytosolic helix linking TMD4-5, which links the voltage-sensor to TMDs forming the pore, leading to twisting of pore-lining helices and opening of the channel.
Structure of Closed Channels
- In closed channels, the residues at the tip of TMD6 come together to form a tepee shape, occluding the channel.
Voltage Sensor Mechanism
- The voltage sensor consists of four positively charged residues on TMD4.
- When the plasma membrane (PM) depolarizes, the positively charged residues on TMD4 move outwards in the plane of the membrane.
- This movement pulls a short cytosolic helix linking TMD4-5, which links the voltage-sensor to TMDs forming the pore.
- The pulling of the cytosolic helix leads to twisting of pore-lining helices and opening of the channel.
Tyrosine Kinases
- There are 85 tyrosine kinases in humans
- Mutations in tyrosine kinases are often oncogenic
Receptor Tyrosine Kinases (RTKs)
- RTKs are activated by binding of extracellular signalling molecules
- Activation of RTKs leads to dimerization of the receptor
- Cytosolic tyrosine kinase activity is activated on the receptor
- Each subunit trans-phosphorylates tyrosine residues on the other
- Phosphorylated tyrosine residues provide docking sites for proteins with SH2 or PTB domains
Insulin Signalling Pathway
- Insulin receptor is a dimer of dimers
- Transphosphorylation of intracellular domains occurs
- IRS1 is recruited to phospho-tyrosine by PTB domain
- SH2 domain of p85 adaptor subunit of PI3K phosphorylates IRS1
- Catalytic domain of PI3K (p110) phosphorylates PIP2 at the 3-position to form PIP3
- PIP3 acts as a scaffold protein, recruiting other proteins such as Akt2 and PDK1
- mTORC2 is recruited in the fed state and phosphorylates Akt2
- Phosphorylated Akt2 inhibits glycogen synthase kinase, stimulating glycogen synthesis
- Akt2 also regulates FOXO, inhibiting gluconeogenesis and up-regulating GLUT4 vesicles and glucose uptake in muscle and adipocytes
Insulin Signalling Pathway
- Insulin receptor is a dimer of dimers, facilitating transphosphorylation of intracellular domains.
- IRS1 is recruited to phospho-tyrosine by its PTB domain, enabling interaction with the insulin receptor.
- The SH2 domain of p85, an adaptor subunit of PI3K, phosphorylates IRS1, activating downstream signalling.
- PI3K's catalytic domain, p110, phosphorylates PIP2 at the 3-position, forming PIP3, which acts as a scaffold protein.
- PIP3 recruits proteins such as Akt2 and PDK1, which bind through their PH domains, facilitating protein-protein interactions.
- In the fed state, mTORC2 is recruited, phosphorylating Akt2, which undergoes a conformational change, becoming a substrate for PDK1.
- PDK1 phosphorylates Akt2 at serine and threonine residues, leading to:
- Inhibition of glycogen synthase kinase, stimulating glycogen synthesis.
- Production of FOXO, which inhibits gluconeogenesis.
- Formation of Rab-GTP, up-regulating GLUT4 vesicles and glucose uptake in muscle and adipocytes.
HIV Infection and Co-receptors
- HIV coat proteins are recognised by a co-receptor in the host membrane, specifically chemokine receptor (GPCR) and CD4 receptor expressed on T-lymphocytes, before infecting cells.
- Maraviroc binds to the recognition site of the CCR5 chemokine receptor, preventing it from binding HIV coat proteins, thereby preventing the virus from infecting T cells.
Water Reabsorption in the Kidney
- Vasopressin/ADH, through the GPCR V2, allows for water reabsorption in the kidney by causing insertion of water channels (aquaporins) into the plasma membrane of collecting tubules.
- Loss of function mutations in the V2 receptor (or in aquaporins) leads to the rare disease, congenital nephrogenic diabetes insipidus.
Thyroid Hormone Regulation
- TSH through a GPCR in the thyroid leads to release of thyroid hormones.
- Mutations in this receptor can lead to constitutive activation of the TSH receptor, resulting in hypothyroidism or thyroid cancers.
G Proteins and GDP/GTP Conversion
- Inactive G proteins have a slow GDP to GTP conversion rate, which is sped up by active G proteins.
- Active GPCRs act as exchange catalysts, facilitating the replacement of GDP with GTP at vacant guanine nucleotide binding sites.
Mutations and Constitutive Activation
- Mutations in the α_s subunit of the Gs protein lead to weak GDP binding, resulting in spontaneous activation.
- In boys with this mutation, the protein is unstable at body temperature but functional in cooler testes, causing constitutive activation of cAMP formation and precocious male puberty.
G-Protein Activity and Regulation
- Intrinsic GTPase activity of the alpha subunit hydrolyzes GTP to GDP, terminating G-protein activity and acting as a molecular clock.
- RGS proteins can accelerate the endogenous GTPase activity of G-proteins, shortening their active lifetime.
Dopamine and GABAB Receptors in Addiction
- Stimulation of dopamine and GABAB receptors (GPCRs) contributes to the rewarding effects of alcohol consumption in addicts.
- These receptors signal through Gi, which inhibits cAMP formation.
- RGS6 enhances the GTPase activity of Gi, and upregulation of RGS6 in alcoholic mice reduces the effectiveness of these receptors.
- RGS6 knockout mice do not become addicted, as the receptors remain effective due to slower G-protein deactivation.
- Inhibitors of RGS6 may provide therapeutic targets for addiction treatment.
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Description
This quiz covers the role of ion channels in neuronal communication, including the flow of ions, membrane potential changes, and their regulation of intracellular activities.
