Developmental regulation of smooth muscle contraction in the urinary bladder
Smooth muscle cells in the urinary bladder are involved in the control of urine filling and emptying. We have used mice to study the contractile regulation of urinary bladder smooth muscle during the fetal period. We found that nerve-induced contractions are mainly dependent on muscarinic receptor activation in the newborn whereas adult bladders are equally dependent on muscarinic and purinergic receptor activation. Muscarinic receptor-induced contractions are due to activation of the M3 subtype in both adults and newborns. Activator calcium is mainly recruited from the extracellular space via L-type calcium channels in both adult and newborn tissue. The contractile machinery of the newborn’s bladder tissue is more sensitive to calcium which enables contractions at lower intracellular and extracellular calcium concentrations. Non-muscle myosin is contributing to the force development in the newborn but is not the cause for the increased calcium sensitivity. The increased calcium sensitivity is due to a lower phosphatase activity and a lower expression of the myosin light chain phosphatase subunit MYPT1. The contractions induced by muscarinic receptor agonists are characterized by increased phasic activity in the newborn. This activity is not dependent on K+ channels, calcium release from the sarcoplasmic reticulum or gap junctional transmission. Muscarinic receptor stimulation activates T-type calcium channels in the newborn bladder but not in the adult. The main sensitizing pathways, involving protein kinase C (PKC) and Rho-kinase, are established in the newborn tissue. The effects of PKC activation on muscarinic receptor-induced responses differ in newborn and adult tissue. The muscarinic receptor-induced response of the newborn is abolished in the presence of high PKC activation (using PDBu) whereas the response is potentiated in the adult. The phasic component of the response in the newborn bladder is particularly inhibited due to activation of PKC.
Source Type:Doctoral Dissertation
Keywords:MEDICINE; Rho-kinase; newborn; cellular signaling; muscarinic receptors; calcium sensitivity; protein kinase C; non-muscle myosin; myosin light chain phosphatase
Date of Publication:01/01/2008