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1 Division of Nephrology, Vanderbilt University Medical Center, Nashville, Tennessee 37232; 2 First Division of Internal Medicine, University of Tokyo, Tokyo 113; and 3 Department of Neurophysiology, Tohoku University School of Medicine, Sendai 980-8575, Japan
Recent studies showed that coexpression of Kir6.1 or
Kir6.2 with the sulfonylurea receptor (SUR1, SUR2A, or SUR2B)
reconstituted an inwardly rectifying, ATP-sensitive K+
channel that was inhibited by glibenclamide (2, 15-17). Here we
report the isolation of a rat homolog of mouse SUR2B (denoted rSUR2B)
from a rat kidney cDNA library. The rSUR2B sequence contains a 4,635-bp
open reading frame that encodes a 1,545-amino acid polypeptide, showing
67% shared identity with SUR1 (a pancreatic 
-cell isoform) and 98%
with both SUR2A (a brain isoform) and SUR2B (a vascular smooth muscle
isoform). Consistent with the predicted structures of other members of
the ATP-binding cassette (ABC) superfamily, the sequence of rSUR2B
contains 17 putative membrane-spanning segments. Also, predicted Walker
A and B consensus binding motifs, present in other ABC members, are
conserved in the rSUR2B sequence. RT-PCR revealed that rSUR2B is widely
expressed in various rat tissues including brain, colon, heart, kidney, liver, skeletal muscle, and spleen. The intrarenal distribution of the
rSUR2B transcript was investigated using RT-PCR and Southern blot of
microdissected tubules. The rSUR2B transcript was detected in proximal
tubule, cortical thick ascending limb, distal collecting tubule,
cortical collecting duct, and outer medullary collecting duct, but not
medullary thick ascending limb. This distal distribution overlaps with
that of ROMK. Coexpression of rSUR2B with ROMK2 cRNA (in 1:10 ratio) in
Xenopus laevis oocytes resulted in whole cell
Ba2+-sensitive K+ currents that were inhibited
by glibenclamide (50% inhibition with 0.2 mM glibenclamide). In
contrast, rSUR2B did not confer significant glibenclamide sensitivity
to oocytes coinjected with ROMK1 or ROMK3. The interaction between
ROMK2 and rSUR2B was further studied by coimmunoprecipitation of in
vitro translated rSUR2B and ROMK2. In agreement with the functional
data, the rSUR2B protein was coimmunoprecipitated with ROMK2 in the
ROMK2-rSUR2B cotranslated samples. Our data demonstrate that ROMK2, but
not ROMK1 and ROMK3, can interact with rSUR2B to confer a
sulfonylurea-sensitive K+ channel, implicating SUR proteins
in forming and regulating renal ATP-sensitive K+ channels.
The ROMK isoform specificity of glibenclamide effects suggests that the
NH2 terminus of the ROMK protein mediates rSUR2B-ROMK2 interactions.
ROMK potassium channel; sulfonylurea receptor; glibenclamide; kidney
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