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Questions and Answers
What is the function of VGCaCs?
How do voltage-gated cation channels allow ions to pass through?
How do Ca2+ channels achieve ion selectivity?
What is the function of nicotinic acetylcholine receptors?
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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?
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How do K+ channels differ from Na+ and Ca2+ channels?
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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?
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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?
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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?
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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?
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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?
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What is the outcome of insulin signalling pathway?
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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?
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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?
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What is the outcome of inhibition of glycogen synthase kinase?
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What is the outcome of the formation of Rab-GTP?
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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?
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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?
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What is the function of the CD4 receptor in relation to HIV?
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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?
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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?
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What is the potential therapeutic application of inhibiting RGS6?
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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.
