When the neurotransmitter acetylcholine is applied to skeletal muscle cells it a

Question

When the neurotransmitter acetylcholine is applied to skeletal muscle cells it activates the acetylcholine receptor that is a calcium ion channel causing the muscle cells to contract. In other words, acetylcholine is an agonist for the receptor. A similar molecule, succinylcholine, has been demonstrated to bind the same acetylcholine receptor on skeletal muscle cells and is sometimes used by surgeons as a muscle relaxant. Why does succinylcholine causes muscle relaxation instead of contraction, as acetylcholine does? In other words, what would you call succinylcholine? You are studying a particular type of cancer. You observe that the cells are expressing higher than normal levels of the activated version of the G protein Ras (i.e., they contain more Ras-GTP than normal). a. Further study shows that the one of the Ras genes has been mutated, would you classify this as the mutation of a tumor-suppressor gene or an oncogene? b. Given your knowledge of the regulation of G proteins, suggest an explanation for how this mutant Ras protein results in more Ras-GTP than normal. In a different cancer you also observe an increase in the activated form of Ras, however, in this case, the mutation has occurred in both copies of a gene encoding a protein that normally interacts with Ras. The mutant forms of the protein no longer interact with Ras and this leads to inappropriate growth. Since the mutation leads to cancer, would this loss of function be an example of an oncogene or a tumor-suppressor? Can you suggest a function for this protein?

Explanation / Answer

Answer 53 --- The mechanism of action of Succinylcholine involves a "persistent" depolarization of the neuromuscular junction. (As does acetylcholine, it combines with the cholinergic receptors of the motor end plate to produce depolarization). This depolarization is caused by Succinylcholine mimicking the effect of acetylcholine but without being rapidly hydrolysed by acetylcholinesterase. This depolarization leads to desensitization.

So, succinylcholine is an antagonist for the cholinergic receptor.

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Answer 54 --

a) The mutation causes an overproduction of Ras, resulting in a gain of function. So, this is a mutation of a proto-oncogene forming an oncogene.

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b) Mutations in ras genes lead to the production of permanently activated Ras proteins. Hence we can see unintended and overactive signaling inside the cell, even in the absence of incoming signals. Ras is a membrane-associated guanine nucleotide-binding protein that is normally activated in response to the binding of extracellular signals, such as growth factors, RTKs (Receptor Tyrosine Kinases), TCR (T-Cell Receptors), etc. Ras acts as a binary signal switch cycling between ON and OFF states, which are characterized in terms of a small molecule, a guanine nucleotide, bound to the protein. In the resting cell, Ras is tightly bound to GDP (Guanosine Diphosphate), which is exchanged for GTP (Guanosine Triphosphate) upon binding of extracellular stimuli to cell membrane receptors. In the GTP-bound form, Ras interacts specifically with so-called effector proteins, thereby initiating cascades of protein-protein interactions that may finally lead to cell proliferation. To return to the inactive OFF state, Ras cleaves off the terminal phosphate moiety, the Gamma-Phosphate, of GTP in an enzymatic process, the intrinsic GTPase reaction. The remaining GDP-bound Ras is no longer able to interact with effectors, it is switched OFF.

But this mutant Ras protein remains constitutively in ON state. GTP-bound Ras recruits and activates Raf. Raf initiates a cascade of protein phosphorylation by first phosphorylating MEKs. Phosphorylated MEK in turn phosphorylates ERKs. Phosphorylated ERK moves from the cytoplasm into the nucleus where it subsequently phosphorylates a number of transcription factors, including the specific transcription factor called Elk1. Phosphorylated transcription factors turn on transcription (gene expression) of specific sets of target genes.

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c) The mutation causes a loss of function in the gene, thus the gene is definitely a tumor-suppressor gene.

The Protein encoded by this tumor-suppressor gene may actually be something like NF-1, which prevents constitutive expression of Ras. The tumour suppressor gene NF1 encodes a Ras-GAP. Thus, its mutation in neurofibromatosis will mean that Ras is less likely to be inactivated.

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