Question

Using a luciferase reporter system in tissue culture cells, researchers from the University of California, San Francisco, found that ethanol stimulates transcription of genes in brain cells possibly involved in adaptive responses to alcohol. This process was found to depend on PKA activation. By analogy to other PKA-dependent transcription activation pathways, describe a possible pathway for this transcription induction. What other proteins would be involved?

Answer 1

Protein Kinase A (PKA) is one of the member of family of enyzmes which is functionally dependent on the levels of the second messenger cyclic-adenomonophopshate (cAMP). It is also commonly known as the cAMP dependent A kinase, therefore it works through the cAMP signalling pathway.

Multiple intracellular signaling pathways regulate gene transcription through PKA. cAMP-dependent protein kinase A (PKA) increases gene expression through the cAMP response element-binding protein (CREB). , CREB is a target for several different signaling pathways. It is a transcription factor - CREB. CREB phosphorylation on Ser-133 promotes activation of CREB and transcription of genes with an upstream cAMP response element (CRE) in cell lines and in primary neuronal cultures.

Hence, the whole PKA-cAMP-CREB axis plays an important role in the nervous system, influencing long term synaptic plasticity and memory changes.

Ethanol and other alcohols stimulate adenylate cyclase activity in various tissues and potentiate its stimulation by some hormones (pls refer https://www.ncbi.nlm.nih.gov/pubmed/167556 and http://jpet.aspetjournals.org/content/301/1/66.long). This causes an increase in cAMP production, which would inturn activate PKA ( sustained translocation of the catalytic subunit of PKA) and increases downstream phosphorylation of CREB and its activation.

As mentioned above, alcohol administration to invitro neuronal cultures increases cAMP production, but this is blocked when we give adenosine receptor antagonists .

From the figure, we can see that CaMK and other protein kinases like PKC could also be involved in this response to ethanol.