Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
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Target Concepts:
Gene/Protein
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Query: UNIPROT:P41181 (
collecting duct
)
5,183
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
The large-conductance Ca
2+
-activated K
+
channel, BK (KCNMA1), is expressed along the connecting tubule (CNT) and cortical
collecting duct
(
CCD
) where it underlies flow- and Ca
2+
-dependent K
+
secretion. Its activity is partially under the control of the mechanosensitive transient receptor potential vanilloid type 4 (TRPV4) Ca
2+
-permeable channel. Recently, we identified three small-/intermediate-conductance Ca
2+
-activated K
+
channels, SK1 (KCNN1), SK3 (
KCNN3
), and IK1 (KCNN4), with notably high Ca
2+
-binding affinities, that are expressed in CNT/
CCD
and may be regulated by TRPV4-mediated Ca
2+
influx. The K
+
-secreting
CCD
mCCDcl1 cells, which express these channels, were used to determine whether SK1/3 and IK1 are activated on TRPV4 stimulation and whether they contribute to Ca
2+
influx and activation of BK. Activation of TRPV4 (GSK1016790A) modestly depolarized the membrane potential and robustly increased intracellular Ca
2+
, [Ca
2+
]
i
Inhibition of both SK1/3 and IK1 by application of apamin and 1-[(2-chlorophenyl)diphenylmethyl]-1H-pyrazole (TRAM-34), respectively, further depolarized the membrane potential and markedly suppressed the TRPV4-mediated rise in [Ca
2+
]
i
Application of BK inhibitor iberiotoxin after activation of TRPV4 without apamin/TRAM-34 also reduced [Ca
2+
]
i
and further intensified membrane depolarization, demonstrating BK involvement. However, the BK-dependent effects on [Ca
2+
]
i
and membrane potential were largely abolished by pretreatment with apamin and TRAM-34, identical to that observed by separately suppressing TRPV4-mediated Ca
2+
influx, demonstrating that SK1/3-IK1 channels potently contribute to TRPV4-mediated BK activation. Our data indicate a direct correlation between TRPV4-mediated Ca
2+
signal and BK activation but where early activation of SK1/3 and IK1 channels are critical to sufficiently enhanced Ca
2+
entry and [Ca
2+
]
i
levels required for activation of BK.
...
PMID:Dynamic coupling between TRPV4 and Ca
2+
-activated SK1/3 and IK1 K
+
channels plays a critical role in regulating the K
+
-secretory BK channel in kidney collecting duct cells. 2827 24
