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).