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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
Transient receptor potential cation channel subfamily V member 4 (TRPV4)-mediated Ca
2+
signaling induces early activation of small/intermediate Ca
2+
-activated K
+
channels, SK3 (KCNN3) and IK1 (
KCNN4
), which leads to membrane hyperpolarization and enhanced Ca
2+
influx, which is critical for subsequent activation of the large conductance Ca
2+
-activated K
+
channel BK (KCNMA1) and K
+
secretion in kidney cortical
collecting duct
(
CCD
) cells. The focus of the present study was to determine if such coordinated hierarchical/sequential activation of these channels in
CCD
was orchestrated within caveolae, a known microcompartment underlying selective Ca
2+
-signaling events in other cells. In K
+
-secreting mouse principal cell (PC) line, mCCDcl1 cells, knockdown of caveolae caveolin-1 (CAV-1) depressed TRPV4-mediated Ca
2+
signaling and activation of SK3, intermediate conductance channel (IK1), and BK. Immunofluorescence colocalization analysis and coimmunoprecipitation assays demonstrated direct coupling of TRPV4 with each of the KCa channels in both mCCDcl1 and whole mouse kidney homogenates. Likewise, extending this analysis to CAV-1 demonstrates colocalization and direct coupling of CAV-1 with TRPV4, SK3, IK1, and BK, providing strong support for coupling of the channels in caveolae microdomains. Furthermore, differential expression of CAV-1 along the
CCD
was apparent where CAV-1 was strongly expressed within and along the cell borders of kidney PCs and intercalated cells (ICs), although significantly less in ICs. It is concluded that caveolae provide a key microdomain in PCs and ICs for coupling of TRPV4 with SK3, IK1, and BK that directly contributes to TRPV4-mediated Ca
2+
signaling in these domains leading to rapid and sequential coupling of TRPV4-SK3/IK1-BK that may play a central role in mediating Ca
2+
-dependent regulation of BK and K
+
secretion.
...
PMID:Caveolae facilitate TRPV4-mediated Ca
2+
signaling and the hierarchical activation of Ca
2+
-activated K
+
channels in K
+
-secreting renal collecting duct cells. 3020 67
