Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving antigen-antibody binding – specific binding protein...
Reexamination Certificate
2001-06-20
2004-04-20
Eyler, Yvonne (Department: 1646)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving antigen-antibody binding, specific binding protein...
C435S320100, C435S325000, C435S069100, C530S350000
Reexamination Certificate
active
06723522
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a protein having an amino acid sequence identical to or substantially identical to an amino acid sequence represented by SEQ ID NO.: 1 (preferably, a protein having the Na
+
—HCO
3
−
cotransporter activity: hereinafter, abbreviated as present protein in some cases) or a salt thereof and a DNA encoding it.
2. Description of the Related Art
The organisms maintain and regulate the intracellular ionic environment so that the cellular functions such as proliferation, differentiation, contraction and secretion can exert to a maximum extent as necessary. In order to regulate the ionic environment to the conditions optimal for existence, there are a plurality of transporter proteins transporting ions such as Na
+
, Ca
2+
, H
+
and HCO
3
−
in a plasma membrane. A Na
+
—HCO
3
−
cotransporter belonging to such the transporter is driven by the concentration gradient of Na
+
inside and outside a cellular membrane, and take one Na
+
into a cell together with one or more HCO
3
−
ions [Cellular Molecular Biology, 3rd edition, translated under supervision by Keiko Nakamura et al., Kyoikusha]. Since the structure of a protein such as an enzyme which functions in cells is greatly affected by pH, there is an optimal pH for the protein function. For that reason, maintenance and regulation of an intracellular pH is extremely important to cells for maintaining homeostasis of the cellular function. Since a Na
+
—HCO
3
−
cotransporter exists in the cell membrane and HCO
3
−
taken into cells by a Na
+
—HCO
3
−
cotransporter neutralizes H
+
in a cytoplasmic sol, it plays an important role in regulating an intracellular pH like a Na
+
—H
+
exchanger [Cellular Molecular Biology, 3rd edition, translated under supervision by Keiko Nakamura et al., Kyoikusha].
In addition, the Na
+
—HCO
3
−
cotransporter is present in a proximal convoluted uriniferous tubule of a kidney and exerts in resorting HCO
3
−
from a glomerulus filtrate in cooperation with a Na
+
—H
+
exchanger [The Journal of Biological Chemistry, 272, 19111 (1997)].
The Na
+
—HCO
3
−
cotransporter plays an important role in maintaining the cell homeostasis at a normal time, and is involved in occurrence of cell disorder at an ischemic time. Since intracellular acidosis is caused by ischemia and a Na
+
—HCO
3
— cotransporter and a Na
+
—H
+
exchanger function in order to regulate the decrease in pH. As a result, the intracellular Na
+
concentration is elevated and the overload of Ca
2+
into cells is caused via a Na
+
—Ca
2+
exchanger. Consequently, this overloaded Ca
2+
is considered to be one of factors causing cell disorder [Basic Research in Cardiology, 91, 191 (1996)].
The kidney-derived Na
+
—HCO
3
−
cotransporter gene has been cloned from an amphibian [Nature, 387, 409(1997)]], a rat [American Journal of Physiology, 274, F425(1998)], and a human being [The Journal of Biological Chemistry, 272, 19111, (1997)]. However, a Na
+
—HCO
3
−
cotransporter gene which is expressed in mainly organs other than kidney such as heart and brain has not hitherto been known.
SUMMARY OF THE INVENTION
The object of the present invention is to provide a protein having an amino acid sequence identical to or substantially identical to an amino acid sequence represented by SEQ ID NO.: 1 (preferably, a protein having the Na
+
—HCO
3
−
cotransporter activity), a partial peptide thereof, or a salt thereof, a DNA encoding a protein having an amino acid sequence identical to or substantially identical to an amino acid sequence represented by the SEQ ID NO.: 1 (preferably, a protein having the Na
+
—HCO
3
−
cotransporter activity), or a partial peptide thereof, a recombinant vector containing the DNA, a transformant harboring the recombinant vector a process for producing a protein having an amino acid sequence identical to or substantially identical to an amino acid sequence represented by the SEQ ID NO.: 1 (preferably, a protein having the Na
+
—HCO
3
−
cotransporter activity), or a salt thereof, an antibody to a protein having an amino acid sequence identical to or substantially identical to an amino acid sequence represented by the SEQ ID NO.: 1 (preferably, a protein having the Na
+
—HCO
3
−
cotransporter activity), a partial peptide thereof, or a salt thereof, a method for screening a compound which alters the Na
+
—HCO
3
−
cotransporter activity of a protein having an amino acid sequence identical to or substantially identical to an amino acid sequence represented by the SEQ ID NO.: 1 (preferably, a protein having the Na
+
—HCO
3
−
cotransporter activity), or a salt thereof, a compound obtained by the screening method, or a salt thereof, and a pharmaceutical composition containing the compound or a salt thereof.
The present inventors studied extensively and, as a result, we isolated a cDNA encoding a Na
+
—HCO
3
−
cotransporter protein specifically expressed in a human-derived heart, analyzed the whole nucleotide sequence and, thereafter, succeeded in expression of it in a cell. And, based on these findings, the present inventors further studied, which resulted in completion of the present invention.
That is, the present invention relates to:
(1) a protein having an amino acid sequence identical to or substantially identical to an amino acid sequence represented by SEQ ID NO.: 1, or a salt thereof,
(2) a protein described in (1) above having a Na
+
—HCO
3
−
cotransporter activity, or a salt thereof,
(3) a partial peptide of the protein described in (1) above, or an amide thereof, or an ester thereof, or a salt thereof,
(4) a DNA containing the DNA having a nucleotide sequence encoding the protein described in (1) above,
(5) the DNA described in (4) above having a nucleotide sequence represented by SEQ ID NO.: 2,
(6) a recombinant vector containing the DNA described in (5) above,
(7) a transformant transformed with the recombinant vector described in (6) above,
(8) a method for producing the protein described in (1) above, or a salt thereof, which comprises culturing the transformant described in above (7), to produce the protein described in (1) above which is accumulated and taken,
(9) an antibody against the protein described in (1) above, or a salt thereof, or the partial peptide described in (3) above, or an amide thereof, or an ester thereof, or a salt thereof,
(10) a method for screening a compound, or a salt thereof, which promotes or inhibits a Na
+
—HCO
3
−
cotransporter activity of the protein described in (1) above, or a salt thereof, or the partial peptide described in (3) above, or an amide thereof, or an ester thereof, or a salt thereof, which comprises using the protein described in (1) above, or a salt thereof, or the partial peptide described in (3) above, or an amide thereof, or an ester thereof, or a salt thereof,
(11) a kit for screening a compound, or a salt thereof, which promotes or inhibits a Na
+
—HCO
3
−
cotransporter activity of the protein described in (1) above, or a salt thereof, or the partial peptide described in (3) above, or an amide thereof, or an ester thereof, or a salt thereof, which comprises the protein described in (1) above, or a salt thereof, or the partial peptide thereof described in (3) above, or an amide thereof, or an ester thereof, or a salt thereof,
(12) a compound or a salt thereof which promotes or inhibits a Na
+
—HCO
3
−
cotransporter activity of the protein described in (1) above, or a salt thereof, or the partial peptide described in claim 3, or an amide thereof, or an ester thereof, or a salt thereof, which is obtainable by using the screening method described in (10) above or the kit for screening d
Kawamoto Tomohiro
Kimura Hiroyuki
Sawada Hidekazu
Eyler Yvonne
Murphy Joseph F.
Takeda Chemical Industries Ltd.
Wenderoth , Lind & Ponack, L.L.P.
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