The prejunctional modulatory receptors can be new targets for pharmacological manipulation of lower urinary tract and also possible sites for pathologically-induced changes that can lead to a disruption of normal voiding function. The experiments in this proposal will evaluate two major questions. The first deals with the intracellular mechanisms (e.g., signal transduction pathways) underlying presynaptic muscarinic and adrenergic facilitation of transmitter release in the urinary bladder of rats and human. We will investigate: (1) the contribution of extracellular calcium entry via different voltage gated calcium channels to presynaptic facilitation, (2) the role of tonic G protein inhibition of calcium channels, (3) the function of intracellularly released calcium with special attention to calcium-induced calcium release, (4) the role of protein kinases and phosphatases. We will extend the investigations to the neurons of the major pelvic ganglion where both the transmitter release and the direct response of calcium channels to the facilitatory processes can be studied. The second major topic deals with the influence of pathology on presynaptic modulation. Changes in presynaptic modulation may occur in hyperactive bladders induced by spinal cord injury, by bladder hyperactivity induced by inflammation, and by aging. It is expected that the proposed experiments will provide new insights into the pathophysiologic mechanisms underlying neurogenic disorders of the bladder and may lead to new pharmacological approaches for the treatment of these disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
7R01DK045741-08
Application #
6730367
Study Section
Special Emphasis Panel (ZRG4-UROL (01))
Program Officer
Mullins, Christopher V
Project Start
1994-09-30
Project End
2003-08-31
Budget Start
2002-09-01
Budget End
2003-08-31
Support Year
8
Fiscal Year
2001
Total Cost
$153,982
Indirect Cost
Name
Baylor College of Medicine
Department
Urology
Type
Schools of Medicine
DUNS #
074615394
City
Houston
State
TX
Country
United States
Zip Code
77030
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Lai, H Henry; Boone, Timothy B; Yang, Guang et al. (2004) Loss of caveolin-1 expression is associated with disruption of muscarinic cholinergic activities in the urinary bladder. Neurochem Int 45:1185-93
Khera, Mohit; Somogyi, George T; Kiss, Susanna et al. (2004) Botulinum toxin A inhibits ATP release from bladder urothelium after chronic spinal cord injury. Neurochem Int 45:987-93
Szell, Eniko A; Somogyi, George T; de Groat, William C et al. (2003) Developmental changes in spontaneous smooth muscle activity in the neonatal rat urinary bladder. Am J Physiol Regul Integr Comp Physiol 285:R809-16
Somogyi, George T; Zernova, Ganna V; Yoshiyama, Mitsuharu et al. (2003) Change in muscarinic modulation of transmitter release in the rat urinary bladder after spinal cord injury. Neurochem Int 43:73-7
Smith, Christopher P; Boone, Timothy B; de Groat, William C et al. (2003) Effect of stimulation intensity and botulinum toxin isoform on rat bladder strip contractions. Brain Res Bull 61:165-71
Somogyi, George T; Yokoyama, Teruhiko; Szell, Eniko A et al. (2002) Effect of cryoinjury on the contractile parameters of bladder strips: a model of impaired detrusor contractility. Brain Res Bull 59:23-8
Sculptoreanu, A; Yoshimura, N; de Groat, W C et al. (2001) Protein kinase C is involved in M1-muscarinic receptor-mediated facilitation of L-type Ca2+ channels in neurons of the major pelvic ganglion of the adult male rat. Neurochem Res 26:933-42
Yamamoto, T; Ghosh, R; De Groat, W C et al. (2001) Facilitation of transmitter release in the urinary bladders of neonatal and adult rats via alpha1-adrenoceptors. Eur J Pharmacol 414:31-5
Szell, E A; Yamamoto, T; de Groat, W C et al. (2000) Smooth muscle and parasympathetic nerve terminals in the rat urinary bladder have different subtypes of alpha(1) adrenoceptors. Br J Pharmacol 130:1685-91

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