Intestinal epithelial cells (IECs) line the surface of intestinal epithelium, where they play important roles in the digestion of food, absorption of nutrients, and protection of the human body from microbial infections, and others. Dysfunction of IECs can cause diseases. The development, maintenance, and functions of IECs are strongly influenced by external nutrition, such as amino acids. Amino acids play important roles in regulating the properties and functions of IECs. In this article, we briefly reviewed the current understanding of the roles of amino acids in the regulation of IECs’ properties and functions in physiological state, including in IECs homeostasis (differentiation, proliferation, and renewal), in intestinal epithelial barrier structure and functions, and in immune responses. We also summarized some important findings on the effects of amino acids supplementation (e.g., glutamine and arginine) in restoring IECs’ and intestine functions in some diseased states. These findings will further our understanding of the important roles of amino acids in the homeostasis of IECs and could potentially help identify novel targets and reagents for the therapeutic interventions of diseases associated with dysfunctional IECs.

Cyclic nucleotides [e.g., cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP)] are ubiquitous second messengers that affect multiple cell functions from maturation of the egg to cell division, growth, differentiation, and death. The concentration of cAMP can be regulated by processes within membrane domains (local regulation) as well as throughout a cell (global regulation). The phosphodiesterases (PDEs) that degrade cAMP have well-known roles in both these processes. It has recently been discovered that ATP-binding cassette (ABC) transporters contribute to both local and global regulation of cAMP. This regulation may require the formation of macromolecular complexes. Some of these transporters are ubiquitously expressed, whereas others are more tissue restricted. Because some PDE inhibitors are also ABC transporter inhibitors, it is conceivable that the therapeutic benefits of their use result from the combined inhibition of both PDEs and ABC transporters. Deciphering the individual contributions of PDEs and ABC transporters to such drug effects may lead to improved therapeutic benefits.

Formation of multiple-protein macromolecular complexes at specialized subcellular microdomains increases the specificity and efficiency of signaling in cells. In this study, we demonstrate that phosphodiesterase type 3A (PDE3A) physically and functionally interacts with cystic fibrosis transmembrane conductance regulator (CFTR) channel. PDE3A inhibition generates compartmentalized cyclic adenosine 3′,5′-monophosphate (cAMP), which further clusters PDE3A and CFTR into microdomains at the plasma membrane and potentiates CFTR channel function. Actin skeleton disruption reduces PDE3A–CFTR interaction and segregates PDE3A from its interacting partners, thus compromising the integrity of the CFTR-PDE3A–containing macromolecular complex. Consequently, compartmentalized cAMP signaling is lost. PDE3A inhibition no longer activates CFTR channel function in a compartmentalized manner. The physiological relevance of PDE3A–CFTR interaction was investigated using pig trachea submucosal gland secretion model. Our data show that PDE3A inhibition augments CFTR-dependent submucosal gland secretion and actin skeleton disruption decreases secretion.