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RECEPTORS AND SIGNAL TRANSDUCTION

Involvement of ryanodine receptors in muscarinic receptor-mediated membrane current oscillation in urinary bladder smooth muscle

¹University Department of Pharmacology, Oxford, United Kingdom; and ²Department of Cell Physiology and ³Department of Molecular Medicine and Clinical Science, Nagoya University Graduate School of Medicine, Nagoya, Japan

Submitted 25 March 2004 ; accepted in final form 13 August 2004

The urinary bladder pressure during micturition consists of two components: an initial, phasic component and a subsequent, sustained component. To investigate the excitation mechanisms underlying the sustained pressure, we recorded from membranes of isolated detrusor cells from the pig, which can be used as a model for human micturition. Parasympathomimetic agents promptly evoke a large transient inward current, and subsequently during its continuous presence, oscillating inward currents of relatively small amplitudes are observed. The two types of inward current are considered to cause the phasic and sustained pressure rises, respectively. Ionic substitution and applications of channel blockers revealed that Ca²⁺-activated Cl^– channels were responsible for the large transient and oscillating inward currents. Furthermore, the inclusion of guanosine 5'-O-(2-thiodiphosphate) in the patch pipette indicates that both inward currents involve G proteins. However, applications of heparin in the patch pipette and of xestospongin C in the bathing solution suggest a signaling pathway other than inositol 1,4,5-trisphosphate (IP₃) operating in the inward current oscillations, unlike the initial transient inward current. This IP₃-independent inward current oscillation system required both sustained Ca²⁺ influx from the extracellular space and Ca²⁺ release from the intracellular stores. These two requirements are presumably SKF-96365-sensitive cation channels and ryanodine receptors, respectively. Experiments with various Ca²⁺ concentrations suggested that Ca²⁺ influx from the extracellular space plays a major role in pacing the oscillatory rhythm. The fact that distinct mechanisms underlie the two types of inward current may help in development of clinical treatments of, for example, urinary incontinence and residual urine volume control.

G proteins; micturition; oscillation; carbachol; SKF-96365

Address for reprint requests and other correspondence: A. F. Brading, University Department of Pharmacology, Oxford OX1 3QT, UK (E-mail: alison.brading{at}pharm.ox.ac.uk)

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