C-Terminal Determinants of Kir4.2 Channel Expression |
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Authors: | Wade L Pearson Serguei N Skatchkov Misty J Eaton Colin G Nichols |
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Institution: | (1) Department of Cell Biology and Physiology, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, Missouri, 63110;(2) Department of Biochemistry, Universidad Central del Caribe School of Medicine, Box 60-327, Bayamon, Puerto Rico, 00960-6032;(3) Department of Physiology, Universidad Central del Caribe School of Medicine, Box 60-327, Bayamon, Puerto Rico, 00960-6032 |
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Abstract: | Inward rectifier potassium (Kir) channels serve important functional and modulatory roles in a wide variety of cells. While
the activity of several members of this channel family are tightly regulated by intracellular messengers such as adenosine
triphosphate, G proteins, protein kinases and pH, other members are tonically active and activity is controlled only by the
expression level of the protein. In a number of Kir channels, sequence motifs have been identified which determine how effectively
the channel is trafficked to and from the plasma membrane. In this report, we identify a number of trafficking determinants
in the Kir4.2 channel. Using mutational analysis, we found that truncation of the C terminus of the protein increased current
density in Xenopus oocytes, although multiple mutations of the C terminus had no effect on current density. Instead, mutation of a unique region
of the channel significantly increased current density. Selective mutation of a putative tyrosine phosphorylation site within
this region mimicked the increase in current, suggesting that tyrosine phosphorylation of the protein increases channel retrieval
from the membrane (or prevents trafficking to the membrane). Mutation of a previously identified trafficking determinant,
K110N, also caused an increase in current density, and combining these mutations caused a multiplicative increase in current,
suggesting that these two mutations increase current by independent mechanisms. These data demonstrate novel determinants
of Kir4.2 channel expression. |
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Keywords: | Endoplasmic reticulum Oocyte Tyrosine phosphorylation Trafficking |
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