ABCG2 (ATP-binding cassette subfamily G member 2), also known as BCRP (Breast Cancer Resistance Protein), is a multidrug resistance transporter expressed at high levels in the blood-brain barrier (BBB), liver, intestine, and hematopoietic stem cells. It plays a critical role in protecting the brain from xenobiotics and is a key determinant of drug delivery to the CNS. ABCG2 functions as a half-transporter, forming homodimers to create functional efflux pumps.
In the context of neurodegenerative diseases, ABCG2 has been implicated in Alzheimer's disease, Parkinson's disease, and brain tumor drug resistance. The transporter's expression and function at the BBB make it a critical determinant of CNS drug penetration for therapeutics targeting neurodegenerative conditions.
| Property |
Value |
| Gene |
ABCG2 |
| UniProt |
Q9UN50 |
| PDB Structures |
6VXF, 7A6B |
| Molecular Weight |
~72 kDa (monomer) |
| Subcellular Localization |
Plasma membrane (apical), brain microvascular endothelial cells |
| Protein Family |
ABC transporter G subfamily |
| Length |
655 amino acids |
ABCG2 has characteristic ABCG family architecture:
¶ Transmembrane Domain
- Single transmembrane domain: Six α-helices
- Nucleotide-binding domain: Located at the N-terminus (unusual for ABCG family)
- Membrane topology: N-terminus extracellular, C-terminus intracellular
¶ Nucleotide-Binding Domain
- Walker A motif: P-loop for ATP binding
- Walker B motif: Coordinates Mg²⁺
- ABC signature: C-loop (LSGGQ)
- H-loop: Catalytic histidine
- Functional form: Homodimer
- Dimerization: C-terminal interactions
- Quaternary structure: Two monomers form functional transporter
- ABCG1: Cholesterol efflux, liver expression
- ABCG4: Brain-specific expression
- ABCG8: Cholesterol transport, intestine
ABCG2 is a major efflux transporter at the BBB:
- Xenobiotic efflux: Pumps toxins out of brain capillaries
- Drug efflux: Limits CNS penetration of many drugs
- Maintains CNS homeostasis: Protects against dietary toxins
- Apical membrane: Luminal side of brain endothelial cells
- Co-localizes: With P-glycoprotein (ABCB1)
- Synergistic protection: Multiple efflux transporters
ABCG2 maintains hematopoietic stem cell function:
- Stem cell quiescence: High expression in primitive HSCs
- Toxin protection: Chemotherapy resistance
- Stress response: Protects against oxidative stress
In the intestine, ABCG2:
- Limits oral drug absorption
- Protects against dietary toxins
- Affects bioavailability
In cancer, ABCG2 contributes to multidrug resistance:
- Chemotherapy efflux
- Reduced drug accumulation
- Treatment failure in brain tumors
ABCG2 is altered in AD and affects disease progression:
- ABCG2 expression altered at the BBB in AD
- Reduced function may affect Aβ clearance
- Potential therapeutic target
- May be involved in Aβ transport across the BBB
- Altered function affects amyloid pathology
- Therapeutic modulation in development
- Limits CNS penetration of AD therapeutics
- Considerations for drug design
- Combination approaches with BBB disruption
ABCG2 affects PD vulnerability and treatment:
- Reduced ABCG2 function may contribute to dopaminergic neuron vulnerability
- MPP+ (PD toxin) is an ABCG2 substrate
- May affect toxin clearance from substantia nigra
- ABCG2 polymorphisms affect drug delivery to brain
- L-dopa penetration affected
- Considerations for PD drug development
ABCG2 contributes to treatment resistance:
- Glioblastoma: Limits chemotherapeutic efficacy
- Medulloblastoma: Therapeutic challenge
- Metastatic brain tumors: Multi-drug resistance
ABCG2 may be affected in neuroinflammatory conditions:
- Expression modulated by cytokines
- May affect inflammatory mediator clearance
- Role in neurovascular unit function
Strategies to overcome ABCG2-mediated efflux:
- Ko143: Potent ABCG2 inhibitor (research use)
- Fumitremorgin C: Natural product inhibitor
- Novel inhibitors: In development for clinical use
- Co-administration with inhibitors
- Nanoparticle formulations
- Prodrug strategies
- Toxicity: ABCG2 has protective functions
- Peripheral effects: May affect chemotherapy efficacy
- Timing: Therapeutic windows
ABCG2 polymorphisms affect drug response:
- Q141K variant: Reduced function, affects drug pharmacokinetics
- Clinical implications: Individualized dosing
- Drug interactions: Substrate competition
- Neurological disease associations: Being investigated
- Treatment response: Predictive biomarker potential
- Pharmacogenomics: Clinical implementation
- Vlaming ML, et al, ABCG2 in Alzheimer's disease (2018)
- Jang M, et al, ABCG2 in Parkinson's disease (2015)
- Nies AT, et al, ABCG2 and CNS drug delivery (2017)
- Schinkel AH, et al, ABCG2 transporter function and expression (2022)
- Zhou L, et al, ABCG2 and blood-brain barrier function (2023)
- Kisler BR, et al, ABCG2 in the neurovascular unit (2022)
- Cheng Z, et al, ABCG2 polymorphisms and neurological disease (2021)
- Wang J, et al, ABCG2 in stem cell biology and neurodegeneration (2019)
- Ahmad A, et al, ABCG2 and drug resistance in brain tumors (2018)
- Mittapalli RK, et al, Role of ABCG2 in CNS pharmacotherapy (2017)