Detrusor overactivity (DO) is a prevalent medical condition. Despite a growing body of research the pathomechanisms of this condition are still poorly understood and available therapy is ineffective. Calcium (Ca2+) entry through voltage dependent calcium channels (VDCCs) is an important factor for mediating urinary bladder smooth muscle (UBSM) contraction as well as for regulation of neurotransmitter release from nerve terminals. Disruption of this fine balance can result in a voiding dysfunction. This proposal focuses on VDCC CaV2.3 (R-type), its distribution and functional significance in rat urinary bladder and sensory micturition reflex pathways in healthy animals and animals with DO. The overall hypothesis for this grant proposal is that DO-induced neuroplasticity of micturition reflex pathways leads to changes in electrophysiological properties that affect the high voltage activated R-type Ca2+ channel subunit. These changes contribute to an alteration of the micturition reflex through affecting Ca2+ signal patterning in UBSM and bladder sensory neurons.
Specific Aim 1 : To determine distribution of (1E CaV2.3 (R-type) channel subunit in micturition reflex pathways and characterize changes in their expression associated with DO.
Specific Aim 2 : To elucidate UBSM and bladder sensory neuron Ca2+ signaling patterns mediated by R-type Ca2+ channels under physiological and pathological conditions.
Specific Aim 3 : To clarify the physiological significance of the R-type Ca2+ channel subunit in micturition. This proposal takes an integrative approach by applying molecular biology, cell imaging, electrophysiology and in vivo and in vitro functional techniques to identify the CaV2.3 channel in the lower urinary tract (LUT) and define its contribution to Ca2+ signaling under physiological and pathological conditions. To our knowledge, this is the first study addressing the specific role of R-type Ca2+ channel in the LUT.

Public Health Relevance

Results from this study will significantly enhance current knowledge on the specific role of R-type Ca2+ channel in the lower urinary tract, and may provide insight into new therapeutic approaches for the treatment of bladder overactivity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01DK079150-05
Application #
8272661
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Rankin, Tracy L
Project Start
2008-08-01
Project End
2013-11-30
Budget Start
2012-06-01
Budget End
2013-11-30
Support Year
5
Fiscal Year
2012
Total Cost
$136,311
Indirect Cost
$10,097
Name
University of Vermont & St Agric College
Department
Pharmacology
Type
Schools of Medicine
DUNS #
066811191
City
Burlington
State
VT
Country
United States
Zip Code
05405
Zvarova, Katarina; Zvara, Peter (2012) Urinary bladder function in conscious rat pups: a developmental study. Am J Physiol Renal Physiol 302:F1563-8