An Emerging Paradigm for ABCC5/MRP5 Function in Human Physiology.

Area of Science:

• Biochemistry
• Molecular Biology
• Genetics

Background:

• The C-subfamily of ATP-binding cassette (ABC) transporters includes proteins with diverse functions, but several, including ABCC5, remain orphan transporters with poorly understood roles.
• While ABCC5 is implicated in multidrug resistance in cancer, its broader physiological functions are increasingly recognized.

Purpose of the Study:

• To review the emerging understanding of human ABCC5, focusing on its physiological roles, substrates, and implications beyond cancer therapy.
• To highlight the importance of ABCC5's endogenous substrate transport and its involvement in various biological processes.

Main Methods:

• Literature review of studies on ABCC5, including research utilizing knockout models (mice, zebrafish, sea urchins) and structural analyses.
• Analysis of findings related to ABCC5's substrate specificity, including cyclic nucleotides, glutamate conjugates, and haem.

Main Results:

• ABCC5 exports endogenous substrates like cAMP, cGMP, NAAG, and haem, influencing gut formation, brain function, eye development, and iron metabolism.
• In mice, ABCC5 deletion affects adipose tissue, insulin sensitivity, and neurobehavior, suggesting roles in glutamatergic signaling and circadian regulation.
• Structural studies revealed an autoinhibitory mechanism in ABCC5, offering potential for inhibitor development.

Conclusions:

• ABCC5 plays significant physiological roles in development, metabolism, neurobiology, and male fertility, extending beyond its known function in cancer multidrug resistance.
• Targeting ABCC5 for cancer therapy requires caution due to its critical underappreciated functions, especially in the brain and male reproductive system.
• Further research into ABCC5's substrate specificity, regulation, and interaction with ABCC12 is crucial for developing effective therapeutic strategies.