Scientists identify sensor protein that underlies bladder control
The protein works in bladder and urinary tract cells to detect bladder fullness; understanding its mechanism may lead to needed treatments.

Date:
October 14, 2020
Source:
Scripps Research Institute
Summary:
Scientists have found that the main sensor protein enabling our
sense of touch also underlies the feeling of having a full bladder
and makes normal bladder function possible. The discovery marks
a key advance in basic neurobiology and may also lead to better
treatments for bladder control and urination problems, which are
common especially among the elderly.



FULL STORY ==========================================================================
A team co-led by scientists at Scripps Research has found that the main
sensor protein enabling our sense of touch also underlies the feeling
of having a full bladder and makes normal bladder function possible.


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The discovery, published Oct. 14 in Nature, marks a key advance in basic neurobiology and may also lead to better treatments for bladder control
and urination problems, which are common especially among the elderly.

"We tend to take urination for granted, and it has been under-studied,
yet it's a huge burden when something goes wrong with this system,"
says the study's lead author Kara Marshall, PhD, a postdoctoral research associate in the Department of Neuroscience at Scripps Research. "Now
we've identified a crucial part of how urination normally works."
Marshall and her colleagues focused in this study on the PIEZO2 protein,
a "mechanosensor" that detects the physical stretching of tissues where
it resides. They found that PIEZO2 is expressed in cells of the bladder
and is necessary for normal urinary continence and functioning in both
mice and humans.

"Who would have imagined that the same mechanosensor protein enabling our
sense of touch also alerts us that our bladder is full?" says co-senior
author Ardem Patapoutian, PhD, Professor and Presidential Endowed Chair
in Neurobiology at the Dorris Neuroscience Center at Scripps Research,
and a Howard Hughes Medical Institute investigator.

In 2010, Patapoutian and his lab first identified PIEZO2 and its sister
protein PIEZO1 as mechanosensors that sense mechanical distortions of
tissues. For that feat, among others, Patapoutian was a co-recipient of
the 2020 Kavli Prize in Neuroscience.



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Like most sensor proteins, the PIEZOs are ion-channel proteins, which
are embedded in their host cell's outer membrane and, when triggered
by a stimulus, allow a flow of charged atoms into the cell. Sensor
ion-channel proteins are usually found in sensory neurons in the skin,
joints and other organs. On a given neuron, when enough of these channels
open to admit ion flows, the neuron will fire a nerve signal to the brain.

For PIEZOs, the stimulus that triggers the opening of the ion channel
is the stretching of the cell membrane due to mechanical forces on the
local tissue.

In studies over the past decade, Patapoutian and his colleagues have shown
that PIEZO2 is expressed is different organs and tissues throughout the
body. For example, they exist in lung tissues to sense lung stretch and
help regulate breathing, in blood vessels to sense blood pressure and
in the skin to mediate the sense of touch.

The new study was a collaboration with Alexander Chesler, PhD, and Carsten Bo"nnemann, MD, senior investigators at the National Institutes of Health.

Chesler and Bo"nnemann, and their colleagues, have been studying people
born with genetic mutations that result in the functional loss of
PIEZO2. These individuals suffer various impairments in sensory pathways
known to be PIEZO2- related.

For the study, NIH investigators found that these PIEZO2-deficient
individuals, in addition to their other sensory deficits, lack the normal
sense of having a full bladder. They typically urinate on a schedule to
avoid incontinence and have trouble completely emptying their bladder
when they do urinate.

Patapoutian, Marshall and their colleagues showed in experiments that
the loss of PIEZO2 has similar effects in mice. The urinary tract uses
PIEZO2 protein in both bladder sensory neurons and in bladder-lining
cells called umbrella cells to detect stretch and facilitate urination, indicating a two-part sensor system. As they determined in experiments,
bladder neurons in mice normally respond robustly with nerve signals when
the bladder is filled but are almost completely silent during bladder
filling if they lack PIEZO2.

The mice lacking PIEZO2 in their lower urinary tracts also showed abnormal urination reflexes in the muscles controlling the urethra, the duct in
which urine flows from the bladder. That suggests that in mice and most
likely in people, the mechanosensor protein is needed both for normal bladder-stretch sensation and for normal urination.

The team is currently following up with research on the distinct
roles of bladder neurons and umbrella cells, and how they signal to
each other. They are also investigating the possible roles of other mechanosensors, such as PIEZO1, in bladder control and urination.

"Mice without PIEZO2 had clear urination deficits, but ultimately were
still able to urinate, so that suggests another mechanosensory protein
may be involved," Marshall says.


========================================================================== Story Source: Materials provided by Scripps_Research_Institute. Note:
Content may be edited for style and length.


========================================================================== Journal Reference:
1. Kara L. Marshall, Dimah Saade, Nima Ghitani, Adam M. Coombs, Marcin
Szczot, Jason Keller, Tracy Ogata, Ihab Daou, Lisa T. Stowers,
Carsten G.

Bo"nnemann, Alexander T. Chesler, Ardem Patapoutian. PIEZO2 in
sensory neurons and urothelial cells coordinates urination. Nature,
2020; DOI: 10.1038/s41586-020-2830-7 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/10/201014140958.htm

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