Role of Ca²⁺ entry and Ca²⁺ stores in atypical smooth muscle cell autorhythmicity in the mouse renal pelvis

Abstract

Background and purpose: Electrically active atypical smooth muscle cells (ASMCs) within the renal pelvis have long been considered to act as pacemaker cells driving pelviureteric peristalsis. We have investigated the role of Ca2+ entry and uptake into and release from internal stores in the generation of Ca2+ transients and spontaneous transient depolarizations (STDs) in ASMCs. Experimental approach: The electrical activity and separately visualized changes in intracellular Ca2+ concentration in typical smooth muscle cells (TSMCs), ASMCs and interstitial cells of Cajal‐like cells (ICC‐LCs) were recorded using intracellular microelectrodes and a fluorescent Ca2+ indicator, fluo‐4. Results: In 1 μM nifedipine, high frequency (10–30 min−1) Ca2+ transients and STDs were recorded in ASMCs, while ICC‐LCs displayed low frequency (1–3 min−1) Ca2+ transients. All spontaneous electrical activity and Ca2+ transients were blocked upon removal of Ca2+ from the bathing solution, blockade of Ca2+ store uptake with cyclopiazonic acid (CPA) and with 2‐aminoethoxy‐diphenylborate (2‐APB). STD amplitudes were reduced upon removal of the extracellular Na+ or blockade of IP3 dependent Ca2+ store release with neomycin or U73122. Blockade of ryanodine‐sensitive Ca2+ release blocked ICC‐LC Ca2+ transients but only reduced Ca2+ transient discharge in ASMCs. STDs in ASMCS were also little affected by DIDS, La3+, Gd3+ or by the replacement of extracellular Cl‐ with isethionate. Conclusions: ASMCs generated Ca2+ transients and cation‐selective STDs via mechanisms involving Ca2+ release from IP3‐dependent Ca2+ stores, STD stimulation of TSMCs was supported by Ca2+ entry through L type Ca2+ channels and Ca2+ release from ryanodine‐sensitive stores. British Journal of Pharmacology (2007) 152, 1248–1259; doi:; published online 29 October 2007

Autonomic and sensory nerve modulation of peristalsis in the upper urinary tract

“…This basic organisation of simple pacemaker oscillations and the 'plateau shape' of the ureteric action potential have drawn parallels with the mechanisms driving cardiac excitation (Hurtado et al, 2010(Hurtado et al, , 2014Zawalinski et al, 1975). However, recent evidence of the ion channel complement of the cells in the ureter (Imaizumi et al, 1989;Lang, 1989;Smith et al, 2002) and renal pelvis (Iqbal et al, 2012;Lang et al, 2007c) and their mechanisms of autorhythmicity (Burdyga and Wray, 2005;Lang et al, 2007b), when compared with atrial and ventricular cardiac cells and the lack of any direct autonomic modulation, makes the analogy somewhat superficial (Santicioli and Maggi, 1998). …”

“…It is now well established that propagating nifedipine-sensitive action potentials and Ca 2+ waves within the TSMCs of the renal pelvis and ureter underlie the contractions that propagate the length of the upper urinary system (Burdyga and Wray, 1999;Lang et al, 2007aLang et al, , 2007b. In contraction-arrested preparations of renal pelvis of the mouse, guinea pig and rat, spontaneous transient depolarisations (STDs) are readily recorded with intracellular microelectrodes in the proximal renal pelvis (Klemm et al, 1999;Lang et al, 1998Lang et al, , 2001Lang et al, , 2007aTsuchida and Suzuki, 1992) while spontaneous slow intracellular Ca 2+ waves are recorded in ASMCs within the adventitial region of the mouse proximal renal pelvis (Lang et al, 2007a(Lang et al, , 2007b.…”

“…In contraction-arrested preparations of renal pelvis of the mouse, guinea pig and rat, spontaneous transient depolarisations (STDs) are readily recorded with intracellular microelectrodes in the proximal renal pelvis (Klemm et al, 1999;Lang et al, 1998Lang et al, , 2001Lang et al, , 2007aTsuchida and Suzuki, 1992) while spontaneous slow intracellular Ca 2+ waves are recorded in ASMCs within the adventitial region of the mouse proximal renal pelvis (Lang et al, 2007a(Lang et al, , 2007b. The discharge of these STDs and Ca 2+ transients in the mouse renal pelvis is dependent on the uptake and release of Ca 2+ from both the endoplasmic reticulum (Lang et al, 2007b and mitochondria (Hashitani et al, 2009) suggesting that STDs are generated upon the flow of Ca 2+ -activated inward currents triggered upon the spontaneous release of Ca 2+ from internal stores.…”

Structure of autorhythmical activity of contractile systems

“…Thus, in rats the frequency of the potential oscillation in myocytes of pelvis and calyx is 27, whereas in the peribladder area-6 per minute. Strictly speaking, they are not pacemakers, and can realize primary pacemaker properties under conditions of isolation or disturbance of conductivity [21][22][23][24][25][26]. Thus, it is here that the basic rhythm also reflects the coordinated activity of many structures, but its frequency does not correspond to the rhythm of the primary pacemaker cells.…”

Inositol 1,4,5-trisphosphate receptors and pacemaker rhythms

“…It has been proposed that the elementary localized Ca 2+ release events from IP 3 Rs can synchronize regenerative Ca 2+ signals across the cell, which then produces rhythmic slow waves of membrane depolarization [36]. In addition, there is also some evidence that Ca 2+ release via IP 3 R is involved in atypical smooth muscle autorhythmicity in the mouse renal pelvis [37].…”