(A) PKA holoenzyme and excess free PKA regulatory (R) subunits cluster at a specific subcellular site (or domain, depicted as a grey shaded area) where microviscosity may be higher than the surroundings. (B) When a cAMP signal is generated, cAMP diffuses from the site of synthesis at the plasma membrane and enters the domain where it binds to PKA holoenzyme to release active catalytic (C) subunits. In addition, cAMP also binds to free, excess R subunits localized within the domain. (C) When cAMP is released from the R subunit it can be readily re-captured by a free R subunits located nearby. cAMP is thus ‘trapped’ locally providing a higher cAMP concentration within the domain compared with the surrounding environment. (D) Eventually, cAMP diffuses out of the nanodomain and C subunits re-associate with R subunits locally. For an explanation of what each symbol represents see Figure 2.