TS6 - Nervous System Flashcards
(57 cards)
How do we know that cones are less sensitive, but much faster than rods?
Comparing responses to light flashes in single rods or cones revealed cones are much less sensitive than rods.
Cones also recover faster than rods and produce an ‘undershoot’ recovery phase.
How do cGMP/GMP concentrations control membrane potential? How was this discovered?
The reduction in cGMP concentration causes closure of the cGMP-gated ion channels in the plasma membrane and the hyperpolarization of the cell.
Discovered using patch-clamp to change the levels of cGMP and monitor channel conductance, as well as cloning of the gene encoding the gated channel (CNG channel).
What disorder is associated with perturbations of latrophilin expression?
ADHD symptoms were shown in a mouse model when latrophilin-3 was knocked out.
How did cloning of the cone opsin genes reveal the molecular basis of human color blindness?
Cloning showed that M- and L-opsins are 96% identical, while S-opsin is only ~40% identical.
Due to the M and L genes being quite new from a gene duplication event, recombination is highly common. Recombination between L- and M-opsin genes at meiosis leads to gene arrangements that produce variant color vision. E.g., unequal crossing over. The M- and L-opsin genes map next to each other on the X chromosomes, hence the predominance of color blindness in males.
How is neuronal migration regulated by FLRT? What four experiments have aided in uncovering this?
FLRTs play important roles in regulating the timing of neuronal migration.
- Stripe assays have shown that Unc5 forms a repulsive interaction with FLRT, whilst latrophilin has an adhesive interaction.
- Point mutations were then used with structure-based protein engineering, such that mutant FLRT could no longer bind Unc5. This stops the repulsive signal, showing that FLRT signals through Unc5 receptors.
- Structural biology was also used to show that FLRT and Unc5 form a ternary complex with Latrophilin, due to Unc5 and Latrophilin having different binding sites on FLRT. XRC showed they form a 2:2:4 super-complex.
The ability to form different complexes allows for different functions as the neuron migrates.
- RNA hybridization assays showed that as neurons migrate, there’s different expression levels of the receptors, implying each complex only has functions as certain stages of migration to aid navigation.
Why was it thought that teneurins in the brain contain toxins?
Why do we have this protein in our brain?
Teneurins are related to TcB/C toxins, and teneurins contain the toxin-domain that is normally located within the barrel structure. But, in teneurins it’s outside and is hence dysfunctional…
Knock-outs in C.elegans showed loss of teneurin leads to defects in development, suggesting it plays a role in cellular interactions with the ECM and cell guidance.
How does high-acuity and color vision work?
Cones are highly concentrated in the fovea at the center of the primate retina, hence why color can be seen best at the center of the visual field and not well at the peripheries.
Describe the structure and function of CNG channels.
Its primary structure resembles that of K+ channels, with 6 TM domains and a pore loop between S5 and S6.
Like K+ channels, functional CNG channels comprise 4 subunits with 4 cGMP binding sites.
Its opening is non-selective (like nicotinic ACh receptors), but due to its reversal potential, Na+ influx exceeds K+ efflux. Hence, the net effect is depolarization when cGMP is bound.
What is the function of microglia?
Immune cells that engulf damaged cells and debris upon activation by injury and during developmental remodeling.
What is the function of astrocytes in postmitotic neuron differentiation?
Facilitate synapse formation
Why are teneurins so unusual in terms of their structure?
They are highly intricate for cell guidance receptors, which a strange knot structure that requires a lot of effort to synthesize.
What is the FLRT-Unc5-Latrophilin supercomplex, and how was it studied?
What did these studies reveal about the supercomplex?
The interaction of FLRTs with Unc5 and LPHN has been shown to promote the repulsion of axons from regions of the developing nervous system that are rich in these proteins.
Multi-angle light scattering (MALS) and NMS was used to study to determine oligomer states of the complex, showing that not all homologues form this super-complex.
This means that the receptors can form higher order complexes (not just 1:1 interactions) and the same protein can engage in different complexes with different functions.
How does lateral inhibition from horizontal cells construct the center-surround receptive fields?
Horizontal cells receive input from multiple photoreceptors.
They provide inhibitory feedback to neighbouring photoreceptors and bipolar cells.
Light stimulation of a central photoreceptor activates horizontal cells.
These inhibit surrounding photoreceptors, reducing their signal transmission.
This enhances contrast between centre and surround, forming an excitatory centre and inhibitory surround receptive field.
How did teneurins evolve? How do we know this?
Horizontal gene transfer during early metazoan evolution.
Half of the gene sequence is related to bacterial toxin proteins whilst the other half is a typical cell guidance receptor.
What is the amyloid-beta hypothesis of Alzheimer’s disease?
According to the hypothesis, beta-amyloid protein is produced naturally in the brain, but in Alzheimer’s disease, it accumulates and forms clumps, called plaques, outside and around nerve cells. These plaques can disrupt communication between nerve cells and lead to inflammation, oxidative stress, and cell death, contributing to the progressive loss of cognitive function and memory that are characteristic of Alzheimer’s disease.
The amyloid-beta hypothesis suggests that reducing the levels of beta-amyloid protein in the brain could prevent or slow the progression of Alzheimer’s disease.
How do we test whether a protein elicits attractive, adhesive or repulsive responses?
The confrontation assay (time-consuming and difficult to quantify)
Stripe assay
What is the function of oligodendrocytes in postmitotic neuron differentiation?
Myelinate axons.
Describe the transduction cascade involved in photon absorption within rod cells. How is the signal amplified?
- Light triggers the isomerization of retinal that causes a conformational change in opsin.
- Transducin is then able to bind opsin and become activated.
- Activated transducin catalyzes the exchange of GDP for GTP, releasing the alpha subunit.
- Alpha-GTP activates phosphodiesterase by sequestering the inhibitory subunits.
- PDE hydrolyzes cGMP to GMP.
- Low cGMP levels result in CNG channel closure, hyperpolarization of the cell, and a decline in glutamate release.
- System reset.
Amplification occurs through 1 rhodopsin activating >20 transducin molecules, each of which can activate PDE.
What are the 2 types of bipolar cells, and how do they respond to glutamate signaling from cones?
There are two major subclasses of bipolar cells, OFF bipolar and ON bipolar.
The hyperpolarization of cones by light results in less glutamate release.
OFF bipolar cells have iGluRs, which become less active due to the reduction in glutamate. This means fewer cations enter the cell and the OFF cell is hyperpolarized.
ON cells have mGluRs that also become less active. This means the inhibitory G proteins are less active and the cation channels are less inhibited, resulting in depolarization of the cell.
Describe the type of vision given by the two types of photoreceptors and where they can be found.
Cones are responsible for high acuity, daylight and colour vision; in primates, cones are concentrated in the fovea, the central part of the retina.
Rods are more numerous, more sensitive to photons, and specialized for night vision.
What is an axon growth cone?
The axon growth cone is a highly dynamic structure that contains a complex network of cytoskeletal filaments, including microtubules and actin filaments.
The growth cone is responsible for guiding the developing axon to its target cell or destination during neural development.
What are the four ‘classical’ axon guidance systems?
Slits (bind Robo receptors)
Netrins (bind DCC and Unc5 receptors)
Ephrins (bind Eph receptors)
Semaphorins (bind Plexins)
Describe the structure of vertebrate retina.
The vertebrate retina is a layered structure made of 5 classes of neurons.
The input layer at the back of the retina consists of photoreceptors that detect photons and convert them to electrical signals.
The output layer comprises retinal ganglion cells, which transmit information from the eye to the brain, making up the optic nerve.
In between are bipolar cells and amacrine cells, whose actions influence the signals transmitted from photoreceptors to bipolar cells and then to RGCs.
Pigment cells at the back of the eye absorb extra photons and prevent light scattering.
Describe the structure and function of rhodopsin.
How does the structure of the subunits relate to its function?
Rhodopsins are the photosensitive molecules in rods.
Each rhodopsin consists of an opsin GPCR protein and a small molecule of retinal that’s covalently attached to a lysine residue in the opsin.
Retinal is the chromophore that exists in two isomers. Photon absorption causes a switch of 11-cis retinal to all-trans retinal, triggering a conformational change in the opsin.
This change opens up a binding site for a heterotrimeric G protein, transducin.
