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UniProt release 2012_07

Published July 11, 2012

Headline

To pee or not to pee

There is a season and a time for every purpose. There is a time to sleep and Nature has done its best to avoid as much as possible to have it interrupted by an urgent need to urinate. During a sound sleep, healthy humans produce less urine than during the daytime and also store more urine, as if bladder had an increased capacity at night. This is not simply due to the fact that we usually drink less at night, since temporal variation in urine production is maintained in subjects who take food and drink equally during 24 hours. This phenomenon is also observed in rodents, with an inverted clock, the active phase being at night and the resting phase during the day.

The contraction of smooth muscles of the urinary bladder on a sensation of fullness leads to micturition. This event is precisely controlled by regulation of the central and peripheral nerves. It has been formerly reported that an increase in connexin-43/GJA1 enhances intercellular electrical and chemical transmission and sensitizes the response of bladder muscles to cholinergic neural stimuli. Connexin-43 is a gap junction protein expressed in the urinary bladder. Gap junctions are channels that directly connect the cytoplasm of two cells, allowing various molecules and ions to pass freely between cells and hence establishing a direct chemical and electrical communication between cells. An increase in connexin-43 levels lead to enhanced intercellular communication and a better response of bladder smooth muscle cells to signals from the nervous system.

Does connexin-43 link urinary bladder capacity to the circadian clock? The answer came from a recent publication by Negoro and al.. The authors measured micturition frequency and urine volume using wild-type and heterozygous connexin-43 knockout mice. Both genotypes show the typical day/night variation, but, while the total urine volume is not significantly different, the heterozygous connexin-43 knockout animals exhibit a higher urine volume voided per micturition. This suggests that connexin-43 does not influence the urine volume, but determines the functional capacity of the urinary bladder. Interestingly, connexin-43 expression exhibits a circadian rhythm. mRNA levels peak at the beginning of the active phase and drop by the end of the night, closely followed by protein levels. Circadian connexin-43 expression seems to be transcriptionally regulated by the direct binding of NR1D1/Rev-erbA-alpha to SP1 sites in a biological clock-dependent manner. Connexin-43 expression levels closely correlate with cell-cell communication rates and show an inverse correlation with urine volume by micturition.

Now the pieces of the puzzle give a coherent, although probably still partial, picture: bladder muscle cells have an internal rhythm that generates an oscillation in gap junction function. During the active phase, the intercellular communication is optimal, the sensation of bladder fullness is readily perceived, and animals frequently urinate small volumes. When resting, the decrease in gap junctions leads to a decreased sensitivity to neuronal signals and hence to an increase in bladder capacity. This limits disturbance of sleep by micturition.

As of this release, this new information has been annotated in connexin-43/GJA1 UniProtKB/Swiss-Prot entries.

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