NOs functions complex -EHJ

http://eurheartj.oxfordjournals.org/content/early/2010/08/24/eurheartj.ehq279.full

P-glycoprotein blood barrier/PO/Drug availability/Anti-cancer

P-glycoprotein

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ATP-binding cassette, sub-family B (MDR/TAP), member 1
Crystallographic structure of the mouse MDR3 protein. The approximate positioning of the protein in the cell membrane is indicated by the blue (extracellular face) and red (cytoplasmic face) lines. The protein is depicted as a rainbow colored cartoon (N-terminus = blue, C-terminus = red). A cyclic peptide inhibitor QZ59 is represented by a space-filling model.[1]
[show]Available structures PDB 3G5U, 3G60, 3G61
Identifiers
Symbols	ABCB1; ABC20; CD243; CLCS; GP170; MDR1; MGC163296; P-gp; PGY1
External IDs	OMIM: 171050 MGI: 97570 HomoloGene: 55496 GeneCards: ABCB1 Gene
[show]Gene Ontology Molecular function • nucleotide binding • transporter activity • ATP binding • xenobiotic-transporting ATPase activity • hydrolase activity • ATPase activity Cellular component • membrane fraction • cell surface • membrane • integral to membrane Biological process • transport • response to drug Sources: Amigo / EGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	5243	18671
Ensembl	ENSG00000085563	ENSMUSG00000040584
UniProt	P08183	Q9QX25
RefSeq (mRNA)	NM_000927	NM_011076
RefSeq (protein)	NP_000918	NP_035206
Location (UCSC)	Chr 7: 86.97 - 87.18 Mb	Chr 5: 8.67 - 8.75 Mb
PubMed search	[1]	[2]

ABCB1 at EBI Gene Expression Atlas
ABCB1 is differentially expressed in 97 experiments [93 up/106 dn]: 26 organism parts: kidney [2 up/0 dn], bone marrow [0 up/2 dn], ...; 29 disease states: normal [10 up/3 dn], glioblastoma [0 up/2 dn], ...; 30 cell types, 22 cell lines, 11 compound treatments and 16 other conditions.
Factor Value	Factor	Up/Down
Legend: - number of studies the gene is up/down in
Normal	Disease state	10/3
None	Compound treatment	3/0
Stromal cell	Cell type	1/2
Kidney	Cell type	2/0
MDA-MB-231	Cell line	0/2
Glioblastoma	Disease state	0/2
Epithelial cell	Cell type	0/2
HeLa	Cell line	0/2
Primary	Disease staging	2/0
Bone marrow	Organism part	0/2
ABCB1 expression data in ATLAS

P-glycoprotein (permeability glycoprotein, abbreviated as P-gp or Pgp) is a well-characterized ABC-transporter of the MDR/TAP subfamily.^[2] P-gp is also called ABCB1, ATP-binding cassette sub-family B member 1, MDR1, and PGY1. P-glycoprotein has also recently been designated CD243 (cluster of differentiation 243). In humans, P-glycoprotein is encoded by the ABCB1 gene.^[3]

Pgp is extensively distributed and expressed in the intestinal epithelium, hepatocytes, renal proximal tubular cells, adrenal gland and capillary endothelial cells comprising the blood-brain and blood-testis barrier.

Contents [hide] 1 Function 2 Structure 3 Mechanism 4 Tissue distribution 5 Detecting the activity of the transporter 6 History 7 References 8 Further reading 9 See also 10 External links

[edit] Function

The membrane-associated protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intra-cellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). This protein is a member of the MDR/TAP subfamily. Members of the MDR/TAP subfamily are involved in multidrug resistance. The protein encoded by this gene is an ATP-dependent drug efflux pump for xenobiotic compounds with broad substrate specificity. It is responsible for decreased drug accumulation in multidrug-resistant cells and often mediates the development of resistance to anticancer drugs. This protein also functions as a transporter in the blood-brain barrier.^[4]

ABCB1 is an ATP-dependent efflux pump with broad substrate specificity. It likely evolved as a defense mechanism against harmful substances.

ABCB1 transports various substrates across the cell membrane including:

• Drugs such as colchicine, tacrolimus and quinidine
• Chemotherapeutic agents such as etoposide, doxorubicin, and vinblastine
• Lipids
• Steroids
• Xenobiotics
• Peptides
• Bilirubin
• Cardiac glycosides like digoxin
• Immunosuppressive agents
• Glucocorticoids like dexamethasone
• HIV-type 1 antiretroviral therapy agents like protease inhibitors and nonnucleoside reverse transcriptase inhibitors.

Its ability to transport the above substrates accounts for the many roles of ABCB1 including:

• Regulating the distribution and bioavailability of drugs
  • Increased intestinal expression of P-glycoprotein can reduce the absorption of drugs that are substrates for P-glycoprotein. Thus, there is a reduced bioavailability, and therapeutic plasma concentrations are not attained. On the other hand, supratherapeutic plasma concentrations and drug toxicity may result because of decreased P-glycoprotein expression
  • Active cellular transport of antineoplastics resulting in multidrug resistance to these drugs
• The removal of toxic metabolites and xenobiotics from cells into urine, bile, and the intestinal lumen
• The transport of compounds out of the brain across the blood-brain barrier
• Digoxin uptake
• Prevention of ivermectin entry into the central nervous system
• The migration of dendritic cells
• Protection of hematopoietic stem cells from toxins.^[2]

[edit] Structure

Pgp is a 170 kDa transmembrane glycoprotein, which includes 10-15 kDa of N-terminal glycosylation. The N-term half of the molecule contains 6 transmembrane domains, followed by a large cytoplasmic domain with an ATP-binding site, and then a second section with 6 transmembrane domains and an ATP-binding site that shows over 65% of amino acid similarity with the first half of the polypeptide.^[5] In 2009, the first structure of a mammalian P-glycoprotein was solved (3G5U).^[6] The structure was derived from the mouse MDR3 gene product heterologously expressed in Pichia pastoris yeast. The structure of mouse P-gp is similar to structures of the bacterial ABC transporter MsbA (3B5W and 3B5X) ^[7] that adopt an inward facing conformation that is believed to be important for binding substrate along the inner leaflet of the membrane. Additional structures (3G60 and 3G61) of P-gp were also solved revealing the binding site(s) of two different cyclic peptide substrate/inhibitors. The promiscuous binding pocket of P-gp is lined with aromatic amino acid side chains.

[edit] Mechanism

Binding of a substrate and ATP molecule occur simulatenously. Following binding of each, ATP hydrolysis shifts the substrate into a position to be excreted from the cell. Release of the phosphate (from the original ATP molecule) occurs concurrently with substrate excretion. ADP is released, and a new molecule of ATP binds to the secondary ATP-binding site. Hydrolysis and release of ADP and a phosphate molecule resets the protein.

[edit] Tissue distribution

P-glycoprotein is expressed primarily in certain cell types in the liver, pancreas, kidney, colon, and jejunum.^[8]

[edit] Detecting the activity of the transporter

The activity of the transporter can be determined by both membrane ATPase and cellular calcein assays.

The ABCB1 Transporter is also used to differentiate Transitional B-cells from Naive B-cells. Dyes such as Rhodamine123 and MitoTracker Dyes from Invitrogen can be used to make this differentiation. ^[9]

[edit] History

ABCB1 was first cloned and characterized using its ability to confer a multidrug resistance phenotype to cancer cells that had developed resistance to chemotherapy drugs.^[2][10]

In 2001 a procedure for the synthesis of radioactive verapamil was described. This compound can be used for measuring P-glycoprotein function with positron emission tomography.^[11]

Ascending sensory pathway

Lateral medullary syndrome

Vestibulocochlear Nerve

Note: The passway of VII with VIII will are affected by otitis media in disfunction (Palsy). However, VII lesion will never cause vertigo.

Facial nerve

1. Functional distribution of VII nerve
http://www.google.com.hk/imgres?imgurl=http://www3.mdanderson.org/depts/rpi/mmlearn/pmimages/facial_nerve.gif&imgrefurl=http://www3.mdanderson.org/depts/rpi/mmlearn/pmpages/pmschem.html&usg=__Q3jmMYysUGQ2ApyG7EV8XpUcm2Y=&h=430&w=432&sz=56&hl=zh-TW&start=15&tbnid=rKnXGRrLsK3Q1M:&tbnh=131&tbnw=133&prev=/images%3Fq%3Dfacial%2Bnerve%26um%3D1%26hl%3Dzh-TW%26sa%3DN%26biw%3D1004%26bih%3D581%26tbs%3Disch:10%2C348&um=1&itbs=1&iact=hc&vpx=404&vpy=209&dur=10796&hovh=224&hovw=225&tx=134&ty=114&ei=aPlpTNP4HIPZcf-46Y4N&oei=EPlpTJC1IYmWcdqs_I8F&esq=2&page=2&ndsp=15&ved=1t:429,r:2,s:15&biw=1004&bih=581

2. Passway of VII nerve
http://www.google.com.hk/imgres?imgurl=http://www.ncbi.nlm.nih.gov/bookshelf/picrender.fcgi%3Fbook%3Dcm%26part%3DA1914%26blobname%3Dch62f1.jpg&imgrefurl=http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi%3Fbook%3Dcm%26part%3DA1914&usg=__JKMZZ9O0iA710rjnbWqKnSHWW6c=&h=377&w=707&sz=169&hl=zh-TW&start=0&tbnid=AZJUlZ8IjntFdM:&tbnh=105&tbnw=196&prev=/images%3Fq%3Dfacial%2Bnerve%26um%3D1%26hl%3Dzh-TW%26sa%3DN%26biw%3D1004%26bih%3D581%26tbs%3Disch:10%2C31&um=1&itbs=1&iact=rc&dur=360&ei=o_ppTOGAB8-5cYbI4Y8F&oei=T_ppTOSbH8e9cbO-hZAF&esq=3&page=1&ndsp=15&ved=1t:429,r:5,s:0&tx=102&ty=51&biw=1004&bih=581

Induction of P450 - useful for clinical evaluation

http://www.aafp.org/afp/980101ap/cupp.html