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The ATP1A2 gene codes for the Na+,K+-ATPase aka the sodium potassium pump which is required in neurons for nerutransmissions involving propagated alterations in membrane potential. The Na+,K+-ATPase is a cation-transporting integral membrane protein involved in active transport of sodium and potassium ions against their concentration gradients across the cell membrane. For every molecule of ATP consumed, three sodium ions are exported from the cell in exchange for import of two potassium ions. The Na+,K+-ATPase serves many roles, including cell-volume homeostasis as well as maintenance of the membrane potential. In addition, the generated Na+ and K+ gradients drive various secondary active transporters. Since transport of Na+ and K+ across the cell membrane takes place against such steep concentration gradients, the enzyme consumes high amounts of energy: approximately 25–50% of cellular ATP is consumed by the Na+,K+-ATPase .
Mutations in the ATP1A2 gene have been determined to be one the causes of Familial hemiplegic migraine types 1 and 2…..FHM & FHM2. Recent reports have suggested that patients with mutated ATP1A2 genes may be getting these migraines due to “synaptic fatigue” caused directly or indirectly by the mutated Na/K pump. In these cases neuron to neuron synapses require pre-synaptic glutamate release and require glutamate binding to triggered channels (AMPA) on the post synapse leading to channel opening; letting Na+ into the post synaptic cell and also fostering Ca+2 entry via Nmda receptors. It is after these steps that “synaptic fatigue” potentially might occur at the presynaptic membrane due to the mutated Na/K pumps within the synapse region leading to migraines.
A. Hypothetically suggest “in detailed description” two (2) possible models that would explain how defects/changes in the amino acid sequence of the Na+,K+-ATPase membrane protein (due to mutation in the gene) might result in “synaptic fatigue”. In at least one of these 2 proposed models explain how the mutant Na/K pump together with normal synaptic localized Astrocyte activity might be co-involved in causing the abnormal outcome of chronic “synaptic fatigue” associated with and exhibited in these FHM patients. (hint look up role of astrocytes at synapses that release glutamate)
B. Suggest an experiment or experiments to validate or falsify your hypothesis…for one of your posited models.
You are interested in understanding how the neuromuscular junction works. (see figure 11-39–5th ed)
Normally glutamate binding at the post synaptic membrane leads to post synaptic membrane deploarization via Na+ entry into the muscle cell at the Acetylcholine gated cation channel which propagates to nearby voltage-gated Na+ channels leading to more Na entry. As the action potential propagates away from the channel and down the t tubles it ultimately causes Ca+ release from the smooth ER which then Ca+ binds troponin C leading to actin-myosin II contractions of muscle
The normal post synaptic voltage-gated Na+ channel in the muscle cell membrane that responds to the depolarization caused by Na entry at the Acetylcholine gated cation channel typically has the action potential characteristics depicted by the solid red line in (figure 11-29–5th ed). In an experiment of your design you decide to replace this normal voltage gated Na+ channel with a mutant voltage-gated Na+ channel…..coded for by a mutant SCN1A gene
In your experiment you test and discover that this mutated voltage-gated Na+ channel can bind to Na+ ions with equal affinity as the wildtype gated Na+ channel. But when the mutated post synaptic voltage-gated Na+ channel’s membrane potential is measured after adding acetylcholine it only reaches +20mV at 0.5 ms (30mV below the normal Channel’s max level at that time) (see figure 11-29–5th ed) and its downstream propagated depolarization event is severely delayed and hence triggers Calcium release from the smooth ER ….50ms….. later than normal.(see figure 11-30 and 11-39–5th ed)
A. What might have this mutation done to the Na+ channel to alter its ability to reach a max positive membrane potential of +50mV at 0.5 ms. also Based on your previous answer to A. …How and why would this then delay the “continued” propagation of the “next wave” of depolarization needed for Calcium release from the sarcoplasmic reticulim (SER)
B. If we use a lot more, acetylcholine to bind to and open the Acetylcholine gated cation channel at the synapse[see figure 11-39] could this somehow alter the action potential generated by the adjacent mutated voltage gated Na+ channel returning it to normal max membrane potential levels of 50mV levels at 0.5 ms and -20mV levels at 1ms? (see figure 11-29 and 11-30)
C. What clinical effect will this mutation in the voltage gated Na+ channel gene have on a patient regarding them controlling their own skeletal muscles for movement, or controlling the beating of their heart? (chapter 11 but also chapter 15 —see differential effects of acetylcholine ligands on different targets)
You are interested in the function of a protein, Mtm1, that has a PH domain, an SH3 domain, and a PTB domain. Mtm1 functions downstream of the insulin receptor and binds to this receptor in an insulin-dependent fashion via its PTB domain. You create mutant forms of Mtm1 that delete the various protein domains. You find that these mutations do not seem to affect the protein level or folding of Mtm1. You examine the localization of Mtm1 and your results are summarized in Table Q15-2.
In Table Q15-2, the Δ symbol indicates that the following protein domain is deleted. For example, mtm1ΔPH indicates an Mtm1 protein that lacks the PH domain; mtm1ΔPHΔSH3 indicates an mtm1 protein that lacks both the PH domain and the SH3 domain.
A. Given what you know about these three protein domains and the data above, explain the role of the PH, PTB, and SH3 domains in localizing the Mtm1 protein.
B. How might mutating the insulin receptor within its kinase domain impact the localization of the Mtm1 protein….assume the mutant kinase domain is completely non functional
C. Based on the data in the table which mutation would effect Mtm1s normal localization more….mutating the insulin receptor within its kinase domain or mutating a PI-3 kinase within its catalytic domain…..assume both mutants are completely non functional.
D. If we replaced the PTB domains in Mtm1 with SH2 domains how would this change Mtm1s cellular localization process? Would it change …would it stay the same….explain.
The olfactory receptor neurons in frogs resemble those of mammals, in that they express olfactory receptors that are coupled to a G protein. When the G protein is activated, it activates an adenylyl cyclase to produce cAMP, which then opens cyclic-AMP gated cation channels in the plasma membrane. The opening of these channels depolarizes the membrane, leading to the production of an action potential. Your friend is interested in why neurons stop responding to an odor after prolonged exposure to it, a process called adaptation. He has conducted experiments examining the depolarization of the olfactory receptor neuron, the binding of odorant to the receptor, the activation of the G protein, the levels of cAMP in the cell, and the phosphorylation of adenylyl cyclase. His results are summarized in Table Q15-6.
A. What conclusions can be drawn from the above data regarding the adaption mechanism?
B. Based on the data in the table….. What effect on smell would be expected if we created frogs that constitutively expressed an active adenyl cyclase phosphatase in their olfactory cells and exposed them to odorant?Would the cells be able to adapt after prolonged exposure ? Why? or Why not?
C. Based on the data in the table….. What effect on smell would be expected if we created frogs that constitutively expressed an active cAMP phosphodiesterase in their olfactory cells and exposed them to odorant?Would the cells be able to adapt after prolonged exposure ? Why? or Why not?
Actin-binding proteins can modify the properties of actin. You purify an actin-binding protein called Abp. You examine the effect of Abp on actin polymerization by measuring the kinetics of in vitro actin filament formation, in which pure actin is added in the presence and the absence of purified Abp protein. You obtain the results shown in Figure Q16-1.
Further experiments show that Abp binds to the side of actin filaments and preferentially binds to ADP-containing actin filaments. Propose a possible molecular mechanism consistent with the data above.