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My Journey with cAMP‐dependent Protein Kinase

I was first introduced to cAMP‐dependent protein kinase (PKA) when I was just a young scientist at the beginning of my career, and it has remained as a lifelong companion. PKA has taken me from protein chemistry to atomic structures to brain imaging, and the quest for new knowledge is still ongoing. PKA was the second kinase to be discovered, and we solved the first protein kinase structure in 1991. In the subsequent decades we have come to appreciate the highly dynamic features that drive this molecular allosteric switch. In cells the activity of the PKA catalytic subunit is typically packaged as a holoenzyme complex with functionally non‐redundant cAMP‐binding regulatory (R) subunits, and the holoenzymes are localized to specific sites in the cell in close proximity to dedicated substrates. Many dedicated “cAMP signaling islands” exist within one cell, some at the plasma membrane but others at organelles such as the mitochondria and Golgi and in the nucleus, and each is tightly regulated. Nowhere is PKA signaling more complex than in the brain. PKA is ubiquitous in every mammalian cell, and in so many ways has served as the “poster child” for the kinome that contains over 500 proteins. How then can we explain why the Cb subunit lies near the bottom of the Dark Kinome where important protein kinase are buried but not yet studied? The Cb family contains several isoforms that all differ in only their first exon and includes many splice variants. While Cb1 is expressed ubiquitously in most cells at low levels, Cb2 is expressed in lymphoid tissues while the Cb3/4 isoforms are expressed almost exclusively in brain. Indeed ~50% of PKA signaling in the brain is mediated by Cb isoforms. Using the retina with its well‐organized and terminally differentiated neurons as a “window into the brain” we find that Cb isoforms are highly expressed and that Cb is localized differently from Ca. In addition, we find that Cb is localized to mitochondria in contrast to Ca, RIIa, and RIIb, which are all excluded from mitochondria. Four distinct mutations in Cb lead to a complex phenotype that includes cardiac and skeletal defects as well as a polydactyl presentation. These mutations also inhibit Sonic hedgehog (Shh) signaling adding further support to the importance of Cb in neuronal signaling and development. We are our interdisciplinary strategy to explore this new frontier for PKA signaling in the brain.