Cardiac sulfonylurea receptor short form-based channels confer a glibenclamide-insensitive KATP activity

Abstract

The cardiac sarcolemmal ATP-sensitive potassium channel (K ATP ) consists of a Kir6.2 pore and a SUR2 regulatory subunit, which is an ATP-binding cassette (ABC) transporter. K ATP channels have been proposed to play protective roles during ischemic preconditioning. A SUR2 mutant mouse was previously generated by disrupting the first nucleotide-binding domain (NBD1), where a glibenclamide action site was located. In the mutant ventricular myocytes, a non-conventional glibenclamide-insensitive (10 μM), ATP-sensitive current (I KATPn ) was detected in 33% of singlechannel recordings with an average amplitude of 12.3±5.4 pA per patch, an IC 50 to ATP inhibition at 10 μM, and a mean burst duration at 20.6±1.8 ms. Newly designed SUR2-isoform or variantspecific antibodies identified novel SUR2 short forms in the sizes of 28 and 68 kDa in addition to a 150-kDa long form in the sarcolemmal membrane of wild-type (WT) heart. We hypothesized that channels constituted by these short forms that lack NBD1, confer I KATPn . The absence of the long form in the mutant corresponded to loss of the conventional glibenclamide-sensitive K ATP currents (I KATP ) in isolated cardiomyocytes and vascular smooth muscle cells but the SUR2 short forms remained intact. Nested exonic RT-PCR in the mutant indicated that the short forms lacked NBD1 but contained NBD2. The SUR2 short forms co-immunoprecipitated with Kir6.1 or Kir6.2 suggesting that the short forms may function as hemi-transporters reported in other eukaryotic ABC transporter subgroups. Our results indicate that different K ATP compositions may co-exist in cardiac sarcolemmal membrane.

Nicorandil, a Katp channel opener, alleviates chronic renal injury by targeting podocytes and macrophages

“…As shown in Fig. 5J, the cultured human podocytes also express SUR2 and have two isoforms of SUR2, which is consistent with previous studies (2,16,18). These data suggest that nicorandil might directly bind to SUR2 in the podocyte to prevent MnSOD level from a reduction.…”

Impaired exercise tolerance and skeletal muscle myopathy in sulfonylurea receptor-2 mutant mice

“…Taken together, these data suggest that the mild reduction in cardiac function may have limited global effects (22). Of note, Pu et al (20) recently described the existence of additional SUR2 splice variants whose expression is retained in SUR2 mutant mice. It is possible that these SUR2 splice forms contribute to cardiac K ATP channels and that lack of this subset of K ATP channels in Kir6.2-null mice underlies the observed impaired cardiovascular response to exercise.…”

“…These data suggest that these two partner proteins, Kir6.2 and SUR2, have differential effects on skeletal muscle function. These differences may derive from alternative partnering, for example, with Kir6.1 or SUR1, or may also relate to the shorter protein produced from the SUR2 gene (20). Also, the genetic backgrounds of the mice used in these studies differ, and this could account for some differences.…”

The Interaction of Caveolin 3 Protein with the Potassium Inward Rectifier Channel Kir2.1

“…The rabbit antiKir2.1 antibody was generated by using a peptide sequence (388 -401, DDSENGVPESTSTD) from the C terminus of hKir2.1. The antibodies were raised in rabbits and purified as described previously (15). Results from in-house anti-Kir2.1 antibody were confirmed by using commercially available Santa Cruz rabbit anti-Kir2.1 antibody (data not shown), which was shown previously to detect Kir2.1 in rat tissue (28).…”