Phase separation is a physical process in which a solution of components spontaneously segregates into two distinct phases: a condensed phase and a dilute phase. Traditionally explored in engineering, chemistry and physics, this phenomenon is now gaining recognition in biology for its role in the subcellular sequestration of molecular components and the optimization of intracellular chemical reactions. Since the pivotal findings by Clifford Brangwynne, Anthony Hyman and colleagues in 2009 describing the liquid-like nature of P granules, biological phase separation has been implicated in several processes, including the formation of nucleoli and Cajal bodies, the sequestration of RNA, and the pathological condensation of tau in neurodegenerative diseases. Moreover, a study by Maarten Hardenberg and co-workers suggested that up to 40% of the human proteome could undergo phase separation, which underscores the importance of this phenomenon in cellular organization and function.

In 2020, Zhang and colleagues proposed a novel role for protein kinase A (PKA) phase-separated bodies in buffering molecules of cyclic AMP (cAMP). PKA is a tetrameric enzyme composed of a regulatory (R) subunit dimer and a pair of catalytic subunits, and is a crucial regulator of cardiac function. When activated by cAMP, a ubiquitous second messenger that is produced in response to stimulation of the sympathetic nervous system, PKA modulates the force and duration of cardiac contraction. Therefore, the heart requires precise control of sympathetic-mediated regulation to maintain its physiological function. The study by Zhang and colleagues illustrates how PKA phase separation contributes to this modulation by creating membraneless organelles filled with cAMP and the PKA RIα subunit isoform.