Colin Nichols Lab

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

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...

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.

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

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

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

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)

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)

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)

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)

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)

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
A 🧵 1/n

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

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)

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)

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

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)

Check out our new publication "PIP2-driven cytoplasmic domain motions are coupled to Kir2 channel gating" 🧪
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We love it Stephen, thank you! 🧪

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)

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)

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)

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)

Paradoxical Maturity-Onset Diabetes of the Young Arising From Loss-of-Function Mutations in ATP-Sensitive Potassium Channels Pancreatic β-cell ATP-sensitive K+ (KATP) channel closure underlies electrical excitability and insulin release, but loss or inhibition of KATP channels ca

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
A 🧵 1/n

Next Monday! 🧪

Join us today for a new exciting CIMED seminar! 🧪 @osamaharraz.bsky.social

Join us today for a new exciting CIMED seminar! 🧪

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Given that LC8 is a hub protein interacting with multiple proteins besides the dynein complex, the interaction with LC8 proteins is likely to exert various regulatory effects on Kir4.1's biochemical and cellular activities. 5/n

While the biological implications of these interactions are yet to be elucidated, our in vitro functional assays clearly demonstrate that LC8 interaction does modulate channel function. 4/n

A specific LC8 binding site was identified at the very N-terminus of the Kir4.1 protein, and this 8-amino-acid stretch was both necessary and sufficient to interact with LC8 proteins. 3/n

In this report, we first demonstrate that Kir4.1 proteins make direct interactions with dynein light chain I/II (LC8) proteins. 2/n