Question

As a cell biologist for a pharmaceutical company, you are charged with developing a drug to inhibit the cAMP response element binding protein (CREB) pathway. Briefly describe the cascade leading to CREB activation and where one might target a drug to block its activation.

Answer 1

In the presence of cAMP, the R subunit is bound by four molecules of cAMP, allowing the catalytic subunits to dissociate, translocate to the nucleus, and then phosphorylate CREB. CREB then homodimerizes, binds to the CRE (cAMP response element) in the promoter of target genes, and activates transcription. Drugs could be designed that would interrupt signaling anywhere along the pathway. For example, a drug could stabilize the R and C subunit interactions of PKA and block translation into the nucleus. A drug could prevent interaction of cAMP with the R subunit and essentially lead to the same result. Similarly, a drug could have a more downstream action that might prevent phosphorylation of CREB, thus not allowing it to become activated. Another option would be to prevent the required dimerization of CREB, thus preventing its ability to bind DNA. Hope this helped ;)