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Mechanosensitive Channels

Miguel Chapa, Kat Estrada, Alyssa Pacleb

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Great Diversity of Mechanosensitive Channels

◦Auditory Channel

◦Bacterial Channels

◦Cationic channels in nonsensory cells

◦DEG/ENaC/MEC family

◦MS channels in plants

◦Two-pore potassium (K2P) channel

◦TRP channels

◦Piezo channels

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Structure

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Auditory Channels

Located at the tips of the hair cell stereocilia near the points of the tip link insertion

Molecule forming the pore of this channel is yet to be identified

Hair cell receptors work as an elastic gating spring which pulls on a movable channel gate

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Bacterial Channels

Large Mechanosensitive Ion channels (MscL)

◦On average they have 5TM subunits

◦ △G_gating ranges from -25.1 kcal/mol to -142.7 kcal/mol

◦Pressure sensitive pore about 30 Å to 40 Å in diameter

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Bacterial Channels

Small Mechanosensitive Ion channels (MscS)

◦On average they have 7TM subunits

◦ △G_gating ranges from -77.2 kcal/mol to -140.9 kcal/mol

◦Pressure sensitive pore about 13 Å in diameter

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Function

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Gating

Respond to Macroscopic forces

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Gating

Respond to Macroscopic forces

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Gating

Respond to Macroscopic forces

How does this

happen?

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Gating

Microtubule

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Function - Gating

Microtubule

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Gating

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Gating

Microtubule

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Gating

Auditory

Two Theories

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Function - Auditory Stereocilia

Positive ions enter

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Function - Auditory Stereocilia

Positive ions enter

Depolarization!

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Function - MscL: Mechanosensitive Large Conductance

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Function - MscL: Mechanosensitive Large Conductance

Large Conductance: 3 nS

3 nS = 3000 pS

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Function - MscL: Mechanosensitive Large Conductance

Water, ions, and small proteins can pass through

Large Conductance: 3 nS

3 nS = 3000 pS

Bacteria are a little concerned with not bursting.
So the MscL releases solute so the cell won’t lysis.
When the bacterial membrane bends or changes thickness, the channel opens due to a change in protein conformation. This is a membrane-mediated mechanism

Physical impacts or vibrations, though crucial for animals, have little effect on microbes such as E. coli. In comparison, osmotic force greatly affects individual cells or microbes within their aquatic environment. When bacteria is under osmotic downshock, which is during the transition from media of high osmolarity to low, water inflow gives rise to a substantial increase in the turgor pressure, which is capable of bursting the cell envelope. Mechanosensitive channels are major pathways for the release of cytoplasmic solutes to achieve a rapid reduction of the turgor pressure, therefore avoiding lysis. Gene disruption experiments confirmed that either MscL or MscS channels can rescue bacteria from a strong osmotic shock, while a double knockout of both channels lead to lysis.

Proteins contribute to the osmotic thing

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Physiology/ Diseases

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PIEZOs

~2500 amino acids long

24-38 transmembrane helices

form constitutively open channels

mediate touch as well as cardiovascular regulation

(Guo et al. 2017)

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PIEZOs: Mediates Blood Pressure

Baroflex- homeostatic mechanism which functions to keep blood pressure stable

Piezo1 and Piezo2 are BOTH necessary for Baroflex

(Zheng Zeng et al. 2018)

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PIEZOs: Mediates Blood Pressure

Optogenetics

(Zheng Zeng et al. 2018)

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TMHS Mutation- Deafness

(Xiong et al. 2012)

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TMHS Mutation- Deafness

(Xiong et al. 2012)

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TMHS Mutation- Deafness

SEM

(Xiong et al. 2012)

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Neurodevelopmental Disease

KCNK4/TRAAK Mutation

FHEIG (facial dimorphism, hypertrichosis, epilepsy, intellectual disability/developmental delay, gingival overgrowth)

De novo missense mutation in KCNK4/TRAAK
Results in impaired sensitivity of mechanosensitive channel

(Bauer et al. 2018)

While K2P channels are well known to contribute to the resting membrane potential and cellular excitability, their involvement in pathophysiological processes remains largely uncharacterized. We report that de novo missense mutations in KCNK4 cause a recognizable syndrome with a distinctive facial gestalt, for which we propose the acronym FHEIG (facial dysmorphism, hypertrichosis, epilepsy, intellectual disability/developmental delay, and gingival overgrowth).

De novo missense mutation in KCNK4 (also known as TRAAK)
enocodes a two-pore-domain K+ channel (K2P)
belongs to TRAAK/TREK subfamily of K2P channels with are lipid and mechanosensitive (these channels are activated by stretch to produce fast acting currents)
KCNK4/TRAAK is expressed in neuronal cells of CNS and PNS as well as the retina
Symptoms: basically in the acronym that the authors of the paper proposed

Facial dimorphism → hypotonic face (slightly weaker muscles in the face resulting in a “puzzled” look, thin lips, receding chin
Hypertrichosis → excessive hair growth
Gingival hyperplasia/overgrowth → overgrowth of gum tissue around teeth

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Channelopathy

(Bauer et al. 2018)

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Summary

There are a bunch of different kinds of MS channels
MS channels open differently

Linear
Tension
Pressure

MS channels are necessary to both eukaryotes and prokaryotes

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References

◦A. Anishkin and C. Kung (2005) Microbial mechanosensation. Current Opinion in Neurobiology 15, 397-405.

Bauer, Christiane K et al. “Mutations in KCNK4 that Affect Gating Cause a Recognizable Neurodevelopmental Syndrome.” American journal of human genetics vol. 103,4 (2018): 621-630. doi:10.1016/j.ajhg.2018.09.001

Guo, Yusong R, and Roderick MacKinnon. “Structure-Based Membrane Dome Mechanism for Piezo Mechanosensitivity.” ELife, ELife Sciences Publications, Ltd, 12 Dec. 2017, https://elifesciences.org/articles/33660.

◦I.R. Booth, M.D. Edwards, S. Black, U. Schumann and S. Miller (2007) Mechanosensitive channels in bacteria: signs of closure? Nature Reviews Microbiology 5, 431-440.

Xiong, Wei et al. “TMHS is an integral component of the mechanotransduction machinery of cochlear hair cells.” Cell vol. 151,6 (2012): 1283-95. doi:10.1016/j.cell.2012.10.041

◦Zheng, Jie, and Matthew C. Trudeau. Handbook of Ion Channels. CRC Press, 2015.

Zeng, Wei-Zheng, et al. “PIEZOs Mediate Neuronal Sensing of Blood Pressure and the Baroreceptor Reflex.” Science, American Association for the Advancement of Science, 26 Oct. 2018, https://science.sciencemag.org/content/362/6413/464.