The SLC-ome of membrane transport: From molecular discovery to physiology and clinical applications

Membrane transporters are essential for human health, mediating the movement of nutrients, electrolytes, metabolites and other molecules across cellular and organellar membranes. Genes encoding these proteins account for approximately 5.2% of the human protein coding genome. Nearly half of these belong to the solute carriers (SLC) supergroup, the largest class of membrane transport proteins, collectively termed the "SLC-ome." The current SLC-ome comprises 464 SLCs organized into 76 SLC families, of which 24% (111 SLCs) remain orphan transporters with unknown or incompletely characterized function. An additional 52 SLC-like proteins bring the total to 516 membrane transport proteins. SLCs function as molecular gatekeepers, and their dysfunction contributes to a wide spectrum of human diseases, including cancer, diabetes, and immunological, cardiovascular and neurodegenerative disorders. Pathological consequences of SLC defects include hypertension, hyperglycemia, hypercholesterolemia, nutritional deficiencies, metal ion imbalance, oxidative stress, and dysfunction of mitochondria, lysosomes, endoplasmic reticulum and Golgi apparatus. In addition, genetic defects in SLCs are the cause of many rare diseases. Several SLCs require additional subunits to form functional heteromeric complexes, while others exhibit additional or alternative roles, such as acting as transceptors. In this review, we provide updated physiological, structural, mechanistic, and pharmacological insights for each of the 516 human SLC and SLC-like proteins. We also summarize their classification, structural architecture, transport mechanisms and pharmaceutical relevance, and present the most recent SLC gene nomenclature assignments approved by the HUGO Gene Nomenclature Committee (HGNC).