A new class of inhibitors of cAMP-mediated Cl? secretion in rabbit colon, acting by the reduction of cAMP-activated K+ conductance

Lohrmann, E.; Burhoff, I.; Nitschke, Roland; Lang, Hans‐Jochen; Mania, Daniella; Englert, Heinrich C.; Hropot, M.; Warth, Richard; Rohm, W.; Bleich, Markus; Greger, R.

doi:10.1007/bf00704157

Cited by 131 publications

(126 citation statements)

References 29 publications

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“…The co-localization of KCNQ1 and KCNE3 in basolateral membranes and the almost complete loss of C293B-inhibitable currents in kcne3 Ϫ/Ϫ mice now very strongly support a crucial involvement of basolateral KCNQ1/ KCNE3 heteromers in intestinal and tracheal Cl Ϫ secretion. Basolateral cAMP-activated K ϩ channels were proposed to stimulate cAMP-dependent colonic Cl Ϫ secretion by recycling K ϩ for the basolateral NaK2Cl co-transporter NKCC1 and by hyperpolarizing the cell (22,40,41,43). This hyperpolarization counteracts the depolarizing Cl Ϫ efflux through CFTR and increases the electrochemical driving force for apical Cl Ϫ secretion.…”

Section: Discussionmentioning

confidence: 99%

Disruption of the K+ Channel β-Subunit KCNE3 Reveals an Important Role in Intestinal and Tracheal Cl− Transport

Preston

Wartosch

Günzel

et al. 2010

Journal of Biological Chemistry

108

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Section: Discussionmentioning

confidence: 99%

Disruption of the K+ Channel β-Subunit KCNE3 Reveals an Important Role in Intestinal and Tracheal Cl− Transport

Preston

Wartosch

Günzel

et al. 2010

Journal of Biological Chemistry

108

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“…Transepithelial voltage (V te ) was referred to the serosal side. Transepithelial resistance (R te ) was calculated from the voltage deflections (∆V te ) induced by short current pulses every 3 seconds (25 µA, 0.6 sec) (19). The equivalent short circuit current (I sc ) -a measure of electrogenic ion transport -was obtained by Ohm's law from V te /R te .…”

Section: Ussing Chamber Experimentsmentioning

confidence: 99%

P2Y6 receptor mediates colonic NaCl secretion via differential activation of cAMP-mediated transport

Köttgen

Löffler²,

Jacobi³

et al. 2003

J. Clin. Invest.

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“…Most Kv channels are expressed in excitable cells where, e.g., they regulate and modulate the resting potential and the threshold and duration of the action potential (1). The KCNQ1 channel (also called Kv7.1 or KvLQT1) differs from most other Kv channels in that it has key physiological roles in both excitable cells, such as cardiomyocytes (2,3) and pancreatic β-cells (4,5), and in nonexcitable cells, such as in epithelia (3,6). The KCNQ1 channels display diverse biophysical properties in different cell types, a diversity thought to be mainly due to the KCNQ1 channel's association with five tissue-specific, single-transmembrane segment KCNE β-subunits (KCNE1-5) (7-13).…”

mentioning

confidence: 99%

KCNE3 acts by promoting voltage sensor activation in KCNQ1

Barro-Soria

Perez

Larsson

2015

Proc. Natl. Acad. Sci. U.S.A.

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KCNE β-subunits assemble with and modulate the properties of voltage-gated K + channels. In the colon, stomach, and kidney, KCNE3 coassembles with the α-subunit KCNQ1 to form K + channels important for K + and Cl − secretion that appear to be voltageindependent. How KCNE3 subunits turn voltage-gated KCNQ1 channels into apparent voltage-independent KCNQ1/KCNE3 channels is not completely understood. Different mechanisms have been proposed to explain the effect of KCNE3 on KCNQ1 channels. Here, we use voltage clamp fluorometry to determine how KCNE3 affects the voltage sensor S4 and the gate of KCNQ1. We find that S4 moves in KCNQ1/KCNE3 channels, and that inward S4 movement closes the channel gate. However, KCNE3 shifts the voltage dependence of S4 movement to extreme hyperpolarized potentials, such that in the physiological voltage range, the channel is constitutively conducting. By separating S4 movement and gate opening, either by a mutation or PIP 2 depletion, we show that KCNE3 directly affects the S4 movement in KCNQ1. Two negatively charged residues of KCNE3 (D54 and D55) are found essential for the effect of KCNE3 on KCNQ1 channels, mainly exerting their effects by an electrostatic interaction with R228 in S4. Our results suggest that KCNE3 primarily affects the voltage-sensing domain and only indirectly affects the gate.proteins with a variety of crucial physiological roles. Most Kv channels are expressed in excitable cells where, e.g., they regulate and modulate the resting potential and the threshold and duration of the action potential (1). The KCNQ1 channel (also called Kv7.1 or KvLQT1) differs from most other Kv channels in that it has key physiological roles in both excitable cells, such as cardiomyocytes (2, 3) and pancreatic β-cells (4, 5), and in nonexcitable cells, such as in epithelia (3, 6). The KCNQ1 channels display diverse biophysical properties in different cell types, a diversity thought to be mainly due to the KCNQ1 channel's association with five tissue-specific, single-transmembrane segment KCNE β-subunits (KCNE1-5) (7-13). KCNQ1 α-subunit expressed by itself forms a voltage-dependent K + channel that opens at negative voltages ( Fig. 1 A and D). However, coexpression of KCNQ1 with KCNE1 slows the kinetics of activation and shifts the voltage dependence of activation to positive voltages ( Fig. 1 B and D) (7, 8), thereby generating the slowly activating, voltage-dependent I Ks current that controls the repolarization phase of cardiac action potentials. In contrast, coexpression of KCNQ1 with KCNE3 results in a constitutively conducting channel in the physiological voltage range of -80 to +40 mV ( Fig. 1 C and D), which is important for transport of water and salt in epithelial tissues, including those of the colon, small intestine, and airways (9,14,15). In addition, mutations of KCNE3 have been associated with cardiac arrhythmia (16,17) and diseases in the inner ear, such as Meniere's disease and tinnitus (18,19). Because KCNQ1/KCNE3 channels are necessary for water and salt secretion...

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A new class of inhibitors of cAMP-mediated Cl? secretion in rabbit colon, acting by the reduction of cAMP-activated K+ conductance

Cited by 131 publications

References 29 publications

Disruption of the K+ Channel β-Subunit KCNE3 Reveals an Important Role in Intestinal and Tracheal Cl− Transport

Disruption of the K+ Channel β-Subunit KCNE3 Reveals an Important Role in Intestinal and Tracheal Cl− Transport

P2Y6 receptor mediates colonic NaCl secretion via differential activation of cAMP-mediated transport

KCNE3 acts by promoting voltage sensor activation in KCNQ1

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