Expression of a Diverse Array of Ca2+-Activated K+ Channels (SK1/3, IK1, BK) that
Functionally Couple to the Mechanosensitive TRPV4 Channel in the Collecting Duct
System of Kidney
#MMPMID27159616
Li Y
; Hu H
; Butterworth MB
; Tian JB
; Zhu MX
; O'Neil RG
PLoS One
2016[]; 11
(5
): e0155006
PMID27159616
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The voltage- and Ca2+-activated, large conductance K+ channel (BK, maxi-K) is
expressed in the collecting duct system of kidney where it underlies flow- and
Ca2+-dependent K+ excretion. To determine if other Ca2+-activated K+ channels
(KCa) may participate in this process, mouse kidney and the K+-secreting mouse
cortical collecting duct (CCD) cell line, mCCDcl1, were assessed for TRPV4 and
KCa channel expression and cross-talk. qPCR mRNA analysis and immunocytochemical
staining demonstrated TRPV4 and KCa expression in mCCDcl1 cells and kidney
connecting tubule (CNT) and CCD. Three subfamilies of KCa channels were revealed:
the high Ca2+-binding affinity small-conductance SK channels, SK1and SK3, the
intermediate conductance channel, IK1, and the low Ca2+-binding affinity, BK
channel (BK? subunit). Apparent expression levels varied in CNT/CCD where
analysis of CCD principal cells (PC) and intercalated cells (IC) demonstrated
differential staining: SK1:PCIC, IK1:PC>IC, BK?:PC = IC, and
TRPV4:PC>IC. Patch clamp analysis and fluorescence Ca2+ imaging of mCCDcl1 cells
demonstrated potent TRPV4-mediated Ca2+ entry and strong functional cross-talk
between TRPV4 and KCa channels. TRPV4-mediated Ca2+ influx activated each KCa
channel, as evidenced by selective inhibition of KCa channels, with each active
KCa channel enhancing Ca2+ entry (due to membrane hyperpolarization).
Transepithelial electrical resistance (TEER) analysis of confluent mCCDcl1 cells
grown on permeable supports further demonstrated this cross-talk where TRPV4
activation induce a decrease in TEER which was partially restored upon selective
inhibition of each KCa channel. It is concluded that SK1/SK3 and IK1 are highly
expressed along with BK? in CNT and CCD and are closely coupled to TRPV4
activation as observed in mCCDcl1 cells. The data support a model in CNT/CCD
segments where strong cross talk between TRPV4-mediated Ca2+ influx and each KCa
channel leads to enhance Ca2+ entry which will support activation of the low
Ca2+-binding affinity BK channel to promote BK-mediated K+ secretion.
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