ABCC (CFTR/MRP)
Twelve full transporters make up the ABCC subfamily, and they have divergent functional roles that include ion transport, cell-surface receptor, and toxin secretion activities. These transporters are responsible for human diseases, including cystic fibrosis (ABCC7) and pseudoxanthoma elasticum (ABCC6). The cystic fibrosis transmembrane receptor (CFTR/ABCC7) protein functions as a chloride channel that plays a role in exocrine secretion. Different genetic mutations in the CFTR gene cause cystic fibrosis (Quinton, 1999; Rommens et al., 1989). Cystic fibrosis is an (autosomal recessive) disease that may affect the lungs and the digestive system. Mutations in the cystic fibrosis (CF) gene (ABCC7) result in the production of a thick, sticky mucous that can clog up the lungs and sometimes lead to life-threatening infections. In addition, CF can result in obstruction of the pancreas that has the effect of preventing certain enzymes from breaking down and absorbing food into the body (http://www.cff.org). The CF protein has a regulatory domain, otherwise called the R domain, located between NBD1 and TMD2 and contains several potential sites for phosphorylation by cAMP-dependent PKA or PKC. Kinase-mediated phosphorylation of the cytoplasmic R domain is required to transmit the signal from the NBDs to the channel gate. Hence this domain is essential for the functioning of the transporter.
Pseudoxanthoma elasticum (PXE) is an autosomal recessive Mendelian disease that affects multiple body systems caused by mutations in ABCC6 (Bergen et al., 2000). Its main characteristic feature is the mineralization of the soft connective tissue that primarily affects the skin, eyes, and arterial blood vessels. PXE has high phenotypic variability, likely modulated by variants in several modifier genes (K. Moitra et al., 2017). The ABCC8 and ABCC9 proteins bind sulfonylurea and can regulate potassium channels involved in modulating insulin secretion. The additional nine MRP-related genes in this superfamily have diverse functions. ABCC1, ABCC2, and ABCC3 transport drugs conjugated to glutathione and other organic anions. The N-terminal domain (TMD0) is absent in ABCC4, ABCC5, ABCC11, and ABCC12, so these proteins are smaller than the other MRP1-like gene products (Bakos et al., 2000). The remaining ABCC subfamily proteins, ABCC4 and ABCC5, confer resistance to nucleosides, including 9-(2-phosphonylmethoxyethyl) adenine (PMEA) and purine analogs. A recent study found an MRP4 variant (rs3751333) significantly associated with hepatitis B viral DNA level suppression in a cohort of chronic hepatitis B patients treated with entecavir. This result suggests that Han Chinese patients with the rs3751333 GG genotype may respond better to entecavir treatment (Yuan et al., 2016). ABCC4 inhibition, when coupled with phosphodiesterase inhibition in human platelets, convincingly impaired the process of platelet aggregation. The clinical implications of this finding shed light on a crucial relationship between ABCC4 transporter function and phosphodiesterases. The data suggests that the cAMP-directed activity of antithrombotic agents can reduce the occurrence of blood clots (Cheepala et al., 2015).