User:AMonocle/BioProposal

Topic: KCNB1 (Kv2.1) Delayed Rectifiers

URL: https://en.wikipedia.org/wiki/KCNB1

General Organization:

A. Summary (Function)
 * Localized in dendrites and cell body (1)
 * Mediator of apoptosis in hippocampal, cortical and granule neurons (1)
 * Apoptosis function induced by increase in reactive oxygen species (ROS)

B. Structure
 * Functional Alpha Subunit (4), (8)
 * All K+ channels have a pore of alpha-subunits; one to two copies of a conserved loop P-domain
 * P-domain contains selectivity sequence allowing only K+ ions, and only those of a certain class (“functional diversity of families”)
 * Associate with auxiliary cytoplasmic beta subunits
 * 2 types: 6TM spanning regions, 2TM regions
 * 6TM: conserved gene families: Kv, KCNQ, EAG-like, and Ca activated
 * 2TM: inward rectifying
 * Large number of phosphorylation sites (1)

C. Regulation
 * Expression is developmentally regulated (1)
 * Poorly conducting in phosphorylated state (1)

D. Blockers
 * Stromatoxin- voltage-clamp experiments; low selectivity (2)
 * Hanatoxin- inhibits K+ voltage gated channel activation (2)
 * Guangxitoxin- 1E- high selectivity for Kv2 channels (2)

E. Kinetics F. Channelopathies/Mutations G. Physiological Roles in Diseases
 * Repolarization
 * N- and C-terminal regions are main factors in activation kinetics of this channel. (3) (5)
 * Epileptic Encephalopathy (6)
 * Developmental Disabilities
 * Deficiencies in: neurotransmitter regulation, heart rate, insulin production, hearing, etc.
 * Neurodegenerative Diseases: Oxidative modulation of K2.1 channels contributes to altered excitability, progression of neurodegenerative diseases, and healthy aging. (7)
 * Diabetes (Pancreatic Bcell Signaling) : K(+) efflux mediated by KV2.1 delayed rectifier K(+) channels acts as a brake for insulin secretion. (9) (10)
 * Alzheimers: Injury-mediated increased K(+) efflux through Kv2.1 channels promotes neuronal apoptosis, contributing to widespread neuronal loss in neurodegenerative disorders such as Alzheimer's disease. (11)

H. Pharmocology References
 * Anti-apoptotic strategy (1)
 * CO can protect against an increase in KCNC1 current by regulating ROS and PKG
 * Cancer cells and chronic viruses produce excess CO

(1) http://www.wjgnet.com/1949-8454/full/v5/i2/85.htm (2) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3972724/ (3) https://www.ncbi.nlm.nih.gov/pubmed/14608450 (4) https://www.ncbi.nlm.nih.gov/pubmed/12451110 (5) https://www.ncbi.nlm.nih.gov/pubmed/18607586 (6) http://www.pcmicroscopycore.com/the-jordyn-project-kcbn1 (7) https://www.ncbi.nlm.nih.gov/pubmed/25333910 (8) https://www.ebi.ac.uk/interpro/entry/IPR005400 (9) https://www.ncbi.nlm.nih.gov/pubmed/25052376 (10) https://www.ncbi.nlm.nih.gov/pubmed/20711225 (11) https://www.ncbi.nlm.nih.gov/pubmed/24323720