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Colin Nichols Lab

@colinnicholslab.bsky.social

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Posting from Colin Nichols' electrophysiology lab at WashU. Focused on ion channels biophysics & role in physiology and pathology.

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Colin Nichols Lab @colinnicholslab.bsky.social · Jan 28

📢 Nichols Lab is hiring! 📢

Join us at WashU & contribute to cutting-edge ion channel research. DM or email
nicholslab.wustl.edu

Discover our work - Colin Nichols Lab

Welcome to the Vitaly Klyachko Lab! We examine synaptic dysfunction in the brain to better understand Alzheimer’s Disease and Fragile Z Syndrome.

nicholslab.wustl.edu

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Colin Nichols Lab @colinnicholslab.bsky.social · 1d

Check out our new publication "Treatment of overactive KATP channels with glibenclamide in a zebrafish model and a clinical trial in humans with Cantú syndrome" 🧪 @nature.com
www.nature.com/articles/s41...

Treatment of overactive KATP channels with glibenclamide in a zebrafish model and a clinical trial in humans with Cantú syndrome - Scientific Reports

Scientific Reports - Treatment of overactive KATP channels with glibenclamide in a zebrafish model and a clinical trial in humans with Cantú syndrome

www.nature.com

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Colin Nichols Lab @colinnicholslab.bsky.social · 1d

Check out our new publication "Molecular basis of TRPV3 channel blockade by intracellular polyamines" 🧪
www.nature.com/articles/s42...

Molecular basis of TRPV3 channel blockade by intracellular polyamines - Communications Biology

Identification of TRPV3 channel residues interacting with intracellular spermine and high resolution structure of a non-conducting TRPV3 in the presence of NASPM suggest a unifying molecular model to explain spermine block of TRPV1-4 channels.

www.nature.com

Reposted by Colin Nichols Lab

Rockefeller University Press @rupress.org · 1d

In @jgp.org, Scala et al @colinnicholslab.bsky.social assess #SkeletalMuscle properties in gain-of-function knock-in mouse models of Cantu Syndrome. Isolated SUR2 GOF, but not Kir6.1 GOF muscles show enhanced fatiguing that was reversed by the KATP inhibitor glibenclamide

Muscle fatigue arising intrinsically from SUR2- but not Kir6.1-dependent gain-of-function in Cantu syndrome mice

We assessed skeletal muscle properties in GOF knock-in mouse models of Cantu Syndrome. In isolated myofibers there was enhanced Mg-nucleotide activation in

rupress.org

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Colin Nichols Lab @colinnicholslab.bsky.social · 1d

These results shed light on the pathophysiologic relevance of SUR2-dependent KATP channel subunits in skeletal muscle and highlight their role in fatiguing conditions. (6/n)

Colin Nichols Lab @colinnicholslab.bsky.social · 1d

These effects could be prevented in the presence of the KATP channel inhibitor glibenclamide, indicating that the increased fatigue of isolated muscles is a direct consequence of overactive sarcolemmal KATP channels. (5/n)

Colin Nichols Lab @colinnicholslab.bsky.social · 1d

Ex vivo testing of isolated SUR2[A478V], but not Kir6.1[V65M], muscles showed an early onset of fatigue and a marked intra-tetanic decline of force. (4/n)

Colin Nichols Lab @colinnicholslab.bsky.social · 1d

Direct consequences of CS mutations on sarcolemma KATP channels on muscle contractility are currently unclear. Here, we assessed contractility in isolated fast- and slow-twitch muscles from two mouse models of CS, carrying GOF mutations Kir6.1[V65M] or SUR2[A478V]. (3/n)

Colin Nichols Lab @colinnicholslab.bsky.social · 1d

Cantu syndrome (CS) is a rare disease caused by gain-of-function (GOF) mutations of Kir6.1 or SUR2 subunits of ATP-sensitive potassium (KATP) channels. CS patients display a constellation of symptoms, including muscle weakness and fatigue. (2/n)

Colin Nichols Lab @colinnicholslab.bsky.social · 1d

Check out our new publication "Muscle fatigue arising intrinsically from SUR2- but not Kir6.1-dependent gain-of-function in Cantu syndrome mice" 🧪 @rosca26.bsky.social
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Journal of General Physiology @jgp.org · 1d

Scala et al. @colinnicholslab.bsky.social assess #SkeletalMuscle properties in gain-of-function knock-in mouse models of Cantu Syndrome. Isolated SUR2 GOF, but not Kir6.1 GOF muscles showed enhanced fatiguing that was reversed by the KATP channel inhibitor glibenclamide.

Muscle fatigue arising intrinsically from SUR2- but not Kir6.1-dependent gain-of-function in Cantu syndrome mice

We assessed skeletal muscle properties in GOF knock-in mouse models of Cantu Syndrome. In isolated myofibers there was enhanced Mg-nucleotide activation in

rupress.org

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Reposted by Colin Nichols Lab

Rockefeller University Press @rupress.org · 5d

New in @jgp.org: Zangerl-Plessl, Lee, et al. utilized MD simulations to reveal that PIP2 potentiated clockwise twisting motions in individual Kir2 #IonChannel cytoplasmic subunits, as well as concerted dynamics among the four subunits. rupress.org/jgp/article/...
@colinnicholslab.bsky.social

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Colin Nichols Lab @colinnicholslab.bsky.social · 1d

These motions are reduced when PIP2 is removed, leading to narrowing of the critical gate at the M2 helix bundle crossing (HBC), but expansion at the region G-loop, as well as reduced overall fourfold symmetry, in turn coupled to cessation of ion permeation. (5/n)

Colin Nichols Lab @colinnicholslab.bsky.social · 1d

We have carried out full atomistic MD simulations, which indicate PIP2-dependent conformational changes that are coupled to opening and closing of the channel. In the presence of bound PIP2, the cytoplasmic domain performs clockwise twisting motions. (4/n)

Colin Nichols Lab @colinnicholslab.bsky.social · 1d

Most Kir2 channel structures determined in complex with PIP2 molecules are in a closed state, requiring additional conformational changes for channel opening. (3/n)

Colin Nichols Lab @colinnicholslab.bsky.social · 1d

Inwardly rectifying potassium (Kir) channel activity is important in the control of membrane potentials and is regulated through various ligands, including Phosphatidyl-4,5-bisphosphate (PIP2)(2/n)

Colin Nichols Lab @colinnicholslab.bsky.social · 1d

Check out our new publication "PIP2-driven cytoplasmic domain motions are coupled to Kir2 channel gating" 🧪
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Journal of General Physiology @jgp.org · 5d

Eva-Maria Zangerl-Plessl, Sun-Joo Lee, et al. utilized MD simulations to reveal that PIP2 potentiated clockwise twisting motions in individual Kir2 #IonChannel cytoplasmic subunits, as well as concerted dynamics among the four subunits. rupress.org/jgp/article/...
@colinnicholslab.bsky.social

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Colin Nichols Lab @colinnicholslab.bsky.social · 1d

We love it Stephen, thank you! 🧪

Stephen Stone, MD 🔬🧬🐁✏️ @stevestonedraws.bsky.social · 20d

Dr. Colin G. Nichols shared how the KATP channel drives both neonatal diabetes & congenital hyperinsulinism. 🧬 Key insights: SUR1 mutations, shifts in calcium sensitivity, & why diazoxide works (when sulfonylureas may not).
@washumedicine.bsky.social @colinnicholslab.bsky.social #EndoSky

Colin Nichols Lab @colinnicholslab.bsky.social · May 22

Our data provide definitive support for a paradoxical form of MODY associated with KATP channel LOF that is genetically and mechanistically distinct from a late diagnosis of neonatal diabetes resulting from KATP GOF. (5/n)

Colin Nichols Lab @colinnicholslab.bsky.social · May 22

In contrast to the naïve prediction that diabetes should be associated with KATP gain-of-function (GOF, as in KATP-dependent neonatal diabetes), each mutation caused mild to severe loss-of-function (LOF), through distinct molecular mechanisms. (4/n)

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Colin Nichols Lab @colinnicholslab.bsky.social · May 22

We report genotype-phenotype information from a set of patients clinically diagnosed with maturity-onset diabetes of the young (MODY) and carrying coding variants in the KATP regulatory subunit gene ABCC8. (3/n)

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Colin Nichols Lab @colinnicholslab.bsky.social · May 22

Pancreatic β-cell ATP-sensitive K+ (KATP) channel closure underlies electrical excitability and insulin release, but loss or inhibition of KATP channels can lead to paradoxical crossover from hyperinsulinism plus hypoglycemia, to glucose intolerance or diabetes. (2/n)

Colin Nichols Lab @colinnicholslab.bsky.social · May 22

Check out our new publication "Paradoxical Maturity-Onset Diabetes of the Young Arising From Loss-of-Function Mutations in ATP-Sensitive Potassium Channels" 🧪 diabetesjournals.org/diabetes/art... @rosca26.bsky.social
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