Colin Nichols Lab

From Selective Permeation to Physiology in Potassium Channels | Function | American Physiological Society Abstract Highly K+-selective potassium channels are essential for electrical signaling. The high selectivity of most K+ channels, with relative K+: Na+ permeabilities being as high as 100–1000:1 arises from the conserved so-called K+ channel selectivity filter (SF). Structural and computational studies have shown how the SF forms multiple sites that coordinate K+, by mimicking the water dipoles that coordinate K+ ions in solution, and thermodynamically favoring the binding of K+ over Na+. Selective conduction of K+ ions then results from a “knock-on” mechanism, whereby entering ions destabilize the next ion in the file. This review highlights key biophysical and biochemical research that provides insights to the atomic details of these processes. It then discusses how mutations that alter K+ selectivity and permeation in different K+ channels underlie multiple simple and complex diseases, illustrating how selectivity and permeation are central to physiology and to pathophysiology and important for physiologists to be aware of.

Check out our latest review "From Selective Permeation to Physiology in Potassium Channels" 🧪
journals.physiology.org/doi/full/10....

By a chimeric approach, we identify regions of both the very N and C termini of Kir6.1 that are responsible for this isoform specificity effect. 4/n

We addressed the effect of CS SUR2[H60Y] mutation on channel function using DiBAC4(3) membrane potential measurements and found that the mutation uniquely causes a GOF of Kir6.1–SUR2B channels but does not in Kir6.2–SUR2B channels. 3/n

Gain-of-function (GOF) mutations in either Kir6.1 or SUR2 subunits of KATP channels are causally associated with rare Cantu syndrome (CS). 2/n

Cantu syndrome–associated SUR2[H60Y] mutation confers selective gain of function on Kir6.1 ATP-sensitive potassium channels Gain-of-function (GOF) mutations in either Kir6.1 (encoded by KCNJ8) or SUR2 (encoded by ABCC9) are causally associated with Cantu syndrome (CS), characterized by coarse facial appearance, hypertricho...

Check out our new publication "Cantu syndrome–associated SUR2[H60Y] mutation confers selective gain of function on Kir6.1 ATP-sensitive potassium channels" 🧪
www.jbc.org/article/S002...
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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

Muscle fatigue arising intrinsically from SUR2- but not Kir6.1-dependent gain-of-function in Cantu syndrome mice. A new study from Rosa Scala, Colin Nichols et al. @colinnicholslab.bsky.social rupress.org/jgp/article/...

#IonChannels #MolecularPhysiology #Pathophysiology #SkeletalMuscle

PIP2-driven cytoplasmic domain motions are coupled to Kir2 channel gating, say Eva-Maria Zangerl-Plessl, Anna Stary-Weinzinger, Colin G. Nichols, and Sun-Joo Lee rupress.org/jgp/article/...

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#IonChannels #Phospholipids

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
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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/...
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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
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