You are interested in how cyclic-AMP-dependent protein kinase A (PKA) functions

Question

You are interested in how cyclic-AMP-dependent protein kinase A (PKA) functions to affect learning and memory, and you decide to study its function in the brain. It is known that, in the cells you are studying, PKA works via a signal transduction pathway like the one depicted in the figure to the right. Furthermore, it is also known that activated PKA phosphorylates the transcriptional regulator called Nerd that then activates transcription of the gene Brainy. Which situation described below will lead to an increase in Brainy transcription?

Explanation / Answer

The expression of Brainy gene is dependent on a PKA controlled pathway, and the activation of PKA is again cAMP dependent. The pathway given in the figure depicts the mechanism involved in the transcription of Brainy gene, upon activation by the hormone, adrenaline. In brief, adrenaline binds to the G protein coupled receptor, which results in the activation of its subunit. The activated subunit binds and activates adenylate cyclase, which hydrolyze ATP into cAMP. This increases the levels of cAMP inside the cell. Now, the cAMP molecules activate the protein kinase A (PKA), which in turn, enters the nucleus and phoshorylates a transcriptional regulator Nerd. Phosphorylation activates Nerd, and now it binds to the promoter for the gene Brainy, resulting in its transcription.

Now, to increase the transcriptional levels, it would be required to have higher amount of activated regulator Nerd, which can be achieved in turn by high amounts of activated PKA. As mentioned earlier, activation of PKA is dependent on cAMP, hence, high levels of cAMP in the cell, would lead to continuous activation of the PKA, and utlimately increase in gene transcription.

On the other hand, deactivation is a common process to regulate the gene transcription in the cell. This can occur by dephosphorylation of the activated proteins, deactivation of the adenylate cyclase which reduces the levels of cAMP, as well as activation of cAMP phosphodiesterase that converts cAMP into AMP, reducing the amount of cAMP inside the cell.

Any process that can interfere with the deactivation process of transcriptional regulation, would result in increased level of transcription. Thus, among the four situations, a mutation in the cAMP phosphodiesterase encoding gene, which renders the enzyme inactive, would result in high cellular levels of cAMP, and hence increase in transcription of the Brainy gene.

So, the answer is (d)

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