TY - JOUR
T1 - Differential nucleotide regulation of KATP channels by SUR1 and SUR2A
AU - Masia, Ricard
AU - Enkvetchakul, Decha
AU - Nichols, Colin G.
N1 - Funding Information:
We wish to thank Martin Bienengraeber for the generous gift of SUR2A-NBF constructs, and Robert Mercer for advice on methodological issues. Jaeyun Kim and Scott Wu contributed to the generation of the ATPase activity data. This work was supported by Grant HL71232 from the National Institutes of Health (to C.G.N.) and a pre-doctoral fellowship from the American Heart Association (Heartland Affiliate, to R.M.).
PY - 2005/9
Y1 - 2005/9
N2 - ATP-sensitive potassium (KATP) channels are heterooctamers of an inward rectifier potassium channel (Kir6) and a sulfonylurea receptor (SUR, a member of the ATP-binding cassette (ABC) transporter family). In the pancreatic β-cell KATP channels are dynamically active, and transgenic expression of overactive Kir6.2 mutants leads to severe neonatal diabetes and death, while in the ventricular cardiomyocyte they are closed except under conditions of severe metabolic inhibition, and similarly overactive transgenes are without gross phenotypic consequence. This discrepancy may arise in part from differences at the molecular level between the two SUR isotypes that constitute the regulatory subunit of the KATP channel in those tissues: SUR1 in the pancreas, SUR2A in the heart. KATP channels generated from coexpression of Kir6.2 with SUR1 exhibit greater MgADP stimulation than channels generated from coexpression of Kir6.2 with SUR2A. This difference persists when the open state stability of the channel is enhanced by application of PIP2, consistent with each isotype transducing an intrinsically different energetic contribution to the channel pore. When expressed as isolated, affinity-purified protein constructs, NBF2 of SUR1 exhibits increased in vitro ATP hydrolysis compared to NBF2 of SUR2A. This biochemical difference may underlie the increased MgADP stimulation exhibited by SUR1-containing channels vs. SUR2A-containing channels, which may in turn contribute to physiological differences, observed at the tissue level, between pancreatic and cardiac KATP channels.
AB - ATP-sensitive potassium (KATP) channels are heterooctamers of an inward rectifier potassium channel (Kir6) and a sulfonylurea receptor (SUR, a member of the ATP-binding cassette (ABC) transporter family). In the pancreatic β-cell KATP channels are dynamically active, and transgenic expression of overactive Kir6.2 mutants leads to severe neonatal diabetes and death, while in the ventricular cardiomyocyte they are closed except under conditions of severe metabolic inhibition, and similarly overactive transgenes are without gross phenotypic consequence. This discrepancy may arise in part from differences at the molecular level between the two SUR isotypes that constitute the regulatory subunit of the KATP channel in those tissues: SUR1 in the pancreas, SUR2A in the heart. KATP channels generated from coexpression of Kir6.2 with SUR1 exhibit greater MgADP stimulation than channels generated from coexpression of Kir6.2 with SUR2A. This difference persists when the open state stability of the channel is enhanced by application of PIP2, consistent with each isotype transducing an intrinsically different energetic contribution to the channel pore. When expressed as isolated, affinity-purified protein constructs, NBF2 of SUR1 exhibits increased in vitro ATP hydrolysis compared to NBF2 of SUR2A. This biochemical difference may underlie the increased MgADP stimulation exhibited by SUR1-containing channels vs. SUR2A-containing channels, which may in turn contribute to physiological differences, observed at the tissue level, between pancreatic and cardiac KATP channels.
KW - K
KW - NBF
KW - SUR1
KW - SUR2A
UR - http://www.scopus.com/inward/record.url?scp=23644434998&partnerID=8YFLogxK
U2 - 10.1016/j.yjmcc.2005.03.009
DO - 10.1016/j.yjmcc.2005.03.009
M3 - Article
C2 - 15893323
AN - SCOPUS:23644434998
SN - 0022-2828
VL - 39
SP - 491
EP - 501
JO - Journal of Molecular and Cellular Cardiology
JF - Journal of Molecular and Cellular Cardiology
IS - 3
ER -