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Cyclase-associated protein (CAP) has been discovered three decades ago in budding yeast as a protein that associates with the cyclic adenosine monophosphate (cAMP)-producing adenylyl cyclase and that suppresses a hyperactive RAS2 variant. Since that time, CAP has been identified in all eukaryotic species examined and it became evident that the activity in RAS-cAMP signaling is restricted to a limited number of species. Instead, its actin binding activity is conserved among eukaryotes and actin cytoskeleton regulation emerged as its primary function. However, for many years, the molecular functions as well as the developmental and physiological relevance of CAP remained unknown. In the present article, we will compile important recent progress on its molecular functions that identified CAP as a novel key regulator of actin dynamics, i.e., the spatiotemporally controlled assembly and disassembly of actin filaments (F-actin). These studies unraveled a cooperation with ADF/Cofilin and Twinfilin in F-actin disassembly, a nucleotide exchange activity on globular actin monomers (G-actin) that is required for F-actin assembly and an inhibitory function towards the F-actin assembly factor INF2. Moreover, by focusing on selected model organisms, we will review current literature on its developmental and physiological functions, and we will present studies implicating CAP in human pathologies. Together, this review article summarizes and discusses recent achievements in understanding the molecular, developmental and physiological functions of CAP, which led this protein emerge as a novel CAPt’n of actin dynamics.

Actin-based remodeling underlines spine morphogenesis and plasticity and is crucially involved in the processes that constantly reshape the circuitry of the adult brain in response to external stimuli, leading to learning and memory formation and supporting cognitive functions. Hence spine morphology and synaptic strength are tightly linked and indeed abnormalities in spine number and morphology have been described in a number of neurological disorders such as autism spectrum disorders (ASDs), schizophrenia and intellectual disabilities. We have recently demonstrated that the actin regulating protein, Epidermal growth factor receptor pathway substrate 8 (Eps8), is essential for spine growth and long term potentiation. Indeed, mice lacking Eps8 display immature filopodia-like spines, which are unable to undergo potentiation, and are impaired in cognitive functions. Furthermore, reduced levels of Eps8 have been found in the brain of a cohort of patients affected by ASD compared to controls. Here we investigated whether the lack of Eps8, which is also part of the N-methyl-d-aspartate (NMDA) receptor complex, affects the functional maturation of the postsynaptic compartment. Our results demonstrate that Eps8 knock out mice (Eps8 KO) neurons display altered synaptic expression and subunit composition of NMDA receptors (i.e., increased GluN2B-, decreased GluN2A-containing receptors) and impaired GluN2B to GluN2A subunit shift. Indeed Eps8 KO neurons display increased content of GluN2B containing NMDA receptors both at the synaptic and extrasynaptic level. Furthermore, Eps8 KO neurons display an increased content of extra-synaptic GluN2B-containing receptors, suggesting that also the synaptic targeting of NMDA receptors is affected by the lack of Eps8. These data demonstrate that, besides regulation of spine morphogenesis, Eps8 also regulates the synaptic balance of NMDA receptors subunits GluN2A and GluN2B.