Pericytes and the Control of Blood Flow in Brain and Heart

Annual Review of Physiology, Год журнала: 2023, Номер 85(1), С. 137 - 164

Опубликована: Фев. 10, 2023

Pericytes, attached to the surface of capillaries, play an important role in regulating local blood flow. Using optogenetic tools and genetically encoded reporters conjunction with confocal multiphoton imaging techniques, 3D structure, anatomical organization, physiology pericytes have recently been subject detailed examination. This work has revealed novel functions morphological features such as tunneling nanotubes brain microtubes heart. Here, we discuss state our current understanding roles flow control heart, where may differ due distinct spatiotemporal metabolic requirements these tissues. We also outline concept electro-metabolic signaling, a universal mechanistic framework that links tissue regulation by vascular smooth muscle cells, capillary K ATP Kir2.1 channels primary sensors. Finally, present major unresolved questions how they can be addressed.

Язык: Английский

Molecular structure of an open human K _ATP channel

Proceedings of the National Academy of Sciences, Год журнала: 2021, Номер 118(48)

Опубликована: Ноя. 23, 2021

Significance ATP-sensitive potassium channel (K ATP ) modulates membrane excitability according to the intracellular metabolic state: a high ATP/ADP ratio increases by closing K + pore, while low reduces opening it. Such intricate regulation is achieved allowing and ADP act upon two different subunits in that exert opposing effects on channel’s gate. Previous structural studies have focused conformations of with closed pore. This paper presents structure an open pore points specific mechanism allosteric regulation.

Язык: Английский

Structure of an open KATP channel reveals tandem PIP2 binding sites mediating the Kir6.2 and SUR1 regulatory interface

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Март 20, 2024

Abstract ATP-sensitive potassium (K ATP ) channels, composed of four pore-lining Kir6.2 subunits and regulatory sulfonylurea receptor 1 (SUR1) subunits, control insulin secretion in pancreatic β-cells. K channel opening is stimulated by PIP 2 inhibited ATP. Mutations that increase reduce inhibition cause neonatal diabetes. Although considerable evidence has implicated a role for function, previously solved open-channel structures have lacked bound , mechanisms which regulates channels remain unresolved. Here, we report the cryoEM structure harboring diabetes mutation Kir6.2-Q52R, open conformation, to amphipathic molecules consistent with natural C18:0/C20:4 long-chain PI(4,5)P at two adjacent binding sites between SUR1 Kir6.2. The canonical site conserved among -gated Kir channels. non-canonical forms interface SUR1. Functional studies demonstrate both determine activity. pore associated twist cytoplasmic domain rotation N-terminal transmembrane SUR1, widens inhibitory pocket disfavor binding. conformation particularly stabilized Kir6.2-Q52R residue through cation-π bonding SUR1-W51. Together, these results uncover cooperation gating, explain antagonistic regulation ATP, provide putative mechanism stabilizes an

Язык: Английский

Mechanistic insights on KATP channel regulation from cryo-EM structures

The Journal of General Physiology, Год журнала: 2022, Номер 155(1)

Опубликована: Ноя. 9, 2022

Gated by intracellular ATP and ADP, ATP-sensitive potassium (KATP) channels couple cell energetics with membrane excitability in many types, enabling them to control a wide range of physiological processes based on metabolic demands. The KATP channel is complex four subunits from the Kir family, Kir6.1 or Kir6.2, sulfonylurea receptor subunits, SUR1, SUR2A, SUR2B, ATP-binding cassette (ABC) transporter family. Dysfunction underlies several human diseases. importance these health disease has made attractive drug targets. How interact one another how ligands regulate activity have been long-standing questions field. In past 5 yr, steady stream high-resolution structures published using single-particle cryo-electron microscopy (cryo-EM). Here, we review advances bring our understanding regulation pharmacological ligands.

Язык: Английский

Dynamic duo: Kir6 and SUR in K _ATP channel structure and function

Channels, Год журнала: 2024, Номер 18(1)

Опубликована: Март 15, 2024

K

Язык: Английский

Structural insights into the mechanism of pancreatic KATP channel regulation by nucleotides

Nature Communications, Год журнала: 2022, Номер 13(1)

Опубликована: Май 19, 2022

ATP-sensitive potassium channels (KATP) are metabolic sensors that convert the intracellular ATP/ADP ratio to excitability of cells. They involved in many physiological processes and implicated several human diseases. Here we present cryo-EM structures pancreatic KATP channel both closed state pre-open state, resolved same sample. We observe binding nucleotides at inhibitory sites Kir6.2 but not state. Structural comparisons reveal mechanism for ATP inhibition Mg-ADP activation, two fundamental properties channels. Moreover, also uncover activation diazoxide-type openers.

Язык: Английский

KATP channels in focus: Progress toward a structural understanding of ligand regulation

Current Opinion in Structural Biology, Год журнала: 2023, Номер 79, С. 102541 - 102541

Опубликована: Фев. 20, 2023

Язык: Английский

Ligand-mediated Structural Dynamics of a Mammalian Pancreatic KATP Channel

Journal of Molecular Biology, Год журнала: 2022, Номер 434(19), С. 167789 - 167789

Опубликована: Авг. 11, 2022

Язык: Английский

ATP-Sensitive Potassium Channels in Migraine: Translational Findings and Therapeutic Potential

Cells, Год журнала: 2022, Номер 11(15), С. 2406 - 2406

Опубликована: Авг. 4, 2022

Globally, migraine is a leading cause of disability with huge impact on both the work and private life affected persons. To overcome societal burden, better treatment options are needed. Increasing evidence suggests that ATP-sensitive potassium (KATP) channels involved in pathophysiology. These essential blood glucose regulation cardiovascular homeostasis. Experimental infusion KATP channel opener levcromakalim to healthy volunteers patients induced headache attacks 82-100% participants. Thus, this most potent trigger identified date. Levcromakalim likely induces via dilation cranial arteries. However, other neuronal mechanisms also proposed. Here, basic distribution, physiology, pharmacology reviewed followed by thorough review clinical preclinical research involvement migraine. opening blocking have been studied range models and, within recent years, strong importance their has provided from human studies. Despite major advances, translational difficulties exist regarding possible anti-migraine efficacy blockage. due significant species differences potency specificity pharmacological tools targeting various subtypes.

Язык: Английский

Kir6.1 and SUR2B in Cantú syndrome

AJP Cell Physiology, Год журнала: 2022, Номер 323(3), С. C920 - C935

Опубликована: Июль 25, 2022

Kir6.1 and SUR2 are subunits of ATP-sensitive potassium (K ATP ) channels expressed in a wide range tissues. Extensive study has implicated roles these channel diverse physiological functions. Together they generate the predominant K conductance vascular smooth muscle target vasodilatory drugs. Roles for Kir6.1/SUR2 dysfunction disease have been suggested based on studies animal models human genetic discoveries. In recent years, it become clear that gain-of-function (GoF) mutations both genes result Cantú syndrome (CS)—a complex, multisystem disorder. There is currently no targeted therapy CS, but mouse reveal pharmacological reversibility cardiovascular gastrointestinal pathologies can be achieved by administration inhibitor, glibenclamide. Here we review function, structure, pathological Kir6.1/SUR2B channels, with focus CS. Recent led to much improved understanding underlying potential treatment, important questions remain: Can genetically defined CS new insights into function? Do pathophysiological mechanisms may more common diseases? And our armory adequately stocked?

Язык: Английский