Potassium and ANO1/ TMEM16A chloride channel profiles distinguish atypical and typical smooth muscle cells from interstitial cells in the mouse renal pelvis

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Abstract
BACKGROUND AND PURPOSE Although atypical smooth muscle cells (SMCs) in the proximal renal pelvis are thought to generate the pacemaker signals that drive pyeloureteric peristalsis, their location and electrical properties remain obscure. EXPERIMENTAL APPROACH Standard patch clamp, intracellular microelectrode and immunohistochemistry techniques were used. To unequivocally identify SMCs, transgenic mice with enhanced yellow fluorescent protein (eYFP) expressed in cells containing alpha-smooth muscle actin (alpha-SMA) were sometimes used. KEY RESULTS Atypical SMCs were distinguished from typical SMCs by the absence of both a transient 4-aminopyridine-sensitive K+ current (I-KA) and spontaneous transient outward currents (STOCs) upon the opening of large-conductance Ca2+-activated K+ (BK) channels. Many typical SMCs displayed a slowly activating, slowly decaying Cl- current blocked by niflumic acid (NFA). Immunostaining for K(V)4.3 and ANO1/TMEM16A Cl- channel subunits co-localized with alpha-SMA immunoreactive product predominately in the distal renal pelvis. Atypical SMCs fired spontaneous inward currents that were either selective for Cl- and blocked by NFA, or cation-selective and blocked by La3+. alpha-SMA(-) interstitial cells (ICs) were distinguished by the presence of a Xe991-sensitive K(V)7 current, BK channel STOCs and Cl- selective, NFA-sensitive spontaneous transient inward currents (STICs). Intense ANO1/TMEM16A and K(V)7.5 immunostaining was present in Kit(-) alpha-SMA(-) ICs in the suburothelial and adventitial regions of the renal pelvis. CONCLUSIONS AND IMPLICATIONS We conclude that K(V)4.3(+) alpha-SMA(+) SMCs are typical SMCs that facilitate muscle wall contraction, that ANO1/TMEM16A and K(V)7.5 immunoreactivity may be selective markers of Kit(-) ICs and that atypical SMCs which discharge spontaneous inward currents are the pelviureteric pacemakers.