Genetically encoded sensors towards imaging cAMP and PKA activity in vivo

Cyclic adenosine monophosphate (cAMP) is a universal second messenger that plays a crucial role in diverse biological functions, ranging from transcription to neuronal plasticity, and from development to learning and memory. In the nervous system, cAMP integrates inputs from many neuromodulators across a wide range of timescales – from seconds to hours – to modulate neuronal excitability and plasticity in brain circuits during different animal behavioral states. cAMP signaling events are both cell-specific and subcellularly compartmentalized. The same stimulus may result in different, sometimes opposite, cAMP dynamics in different cells or subcellular compartments. Additionally, the activity of protein kinase A (PKA), a major cAMP effector, is also spatiotemporally regulated. For these reasons, many laboratories have made great strides toward visualizing the intracellular dynamics of cAMP and PKA. To date, more than 80 genetically encoded sensors, including original and improved variants, have been published. It is starting to become possible to visualize cAMP and PKA signaling events in vivo, which is required to study behaviorally relevant cAMP/PKA signaling mechanisms. Despite significant progress, further developments are needed to enhance the signal-to-noise ratio and practical utility of these sensors. This review summarizes the recent advances and challenges in genetically encoded cAMP and PKA sensors with an emphasis on in vivo imaging in the brain during behavior.