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Gene/Protein
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Target Concepts:
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Query: UMLS:C0848283 (
rundown
)
502
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Two TMEM16 family members, TMEM16A and TMEM16F, have different ion transport properties. Upon activation by intracellular Ca
2+
, TMEM16A-a Ca
2+
-activated Cl
-
channel-is more selective for anions than cations, whereas TMEM16F-a
phospholipid scramblase
-appears to transport both cations and anions. Under saturating Ca
2+
conditions, the current-voltage (I-V) relationships of these two proteins also differ; the I-V curve of TMEM16A is linear, while that of TMEM16F is outwardly rectifying. We previously found that mutating a positively charged lysine residue (K584) in the ion transport pathway to glutamine converted the linear I-V curve of TMEM16A to an outwardly rectifying curve. Interestingly, the corresponding residue in the outwardly rectifying TMEM16F is also a glutamine (Q559). Here, we examine the ion transport functions of TMEM16 molecules and compare the roles of K584 of TMEM16A and Q559 of TMEM16F in controlling the rectification of their respective I-V curves. We find that rectification of TMEM16A is regulated electrostatically by the side-chain charge on the residue at position 584, whereas the charge on residue 559 in TMEM16F has little effect. Unexpectedly, mutation of Q559 to aromatic amino acid residues significantly alters outward rectification in TMEM16F. These same mutants show reduced Ca
2+
-induced current
rundown
(or desensitization) compared with wild-type TMEM16F. A mutant that removes the
rundown
of TMEM16F could facilitate the study of ion transport mechanisms in this
phospholipid scramblase
in the same way that a CLC-0 mutant in which inactivation (or closure of the slow gate) is suppressed was used in our previous studies.
...
PMID:Comparison of ion transport determinants between a TMEM16 chloride channel and phospholipid scramblase. 3067 Apr 76
TMEM16F is activated by elevated intracellular Ca
2+
, and functions as a small-conductance ion channel and as a
phospholipid scramblase
. In contrast to its paralogs, the TMEM16A/B calcium-activated chloride channels, mouse TMEM16F has been reported as a cation-, anion-, or non-selective ion channel, without a definite conclusion. Starting with the Q559K mutant that shows no current
rundown
and less outward rectification in excised patch, we found that the channel shifted its ion selectivity in response to the change of intracellular Ca
2+
concentration, with an increased permeability ratio of Cl
-
to Na
+
(P
Cl-
/P
Na+
) at a higher Ca
2+
level. The gradual shift of relative ion permeability did not correlate with the channel activation state. Instead, it was indicative of an alteration of electrostatic field in the permeation pathway. The dynamic change of ion selectivity suggests a charge-screening mechanism for TMEM16F ion conduction, and it provides hints to further studies of TMEM16F physiological functions.
...
PMID:Dynamic change of electrostatic field in TMEM16F permeation pathway shifts its ion selectivity. 3131 30
