Unifying Mechanism of Controlling Kir3 Channel Activity by G Proteins and Phosphoinositides

Diomedes E. Logothetis; Rahul Mahajan; Scott K. Adney; Junghoon Ha; Takeharu Kawano; Xuan Yu Meng; Meng Cui

doi:10.1016/bs.irn.2015.05.013

Unifying Mechanism of Controlling Kir3 Channel Activity by G Proteins and Phosphoinositides

Diomedes E. Logothetis^*, Rahul Mahajan, Scott K. Adney, Junghoon Ha, Takeharu Kawano, Xuan Yu Meng, Meng Cui

^*Corresponding author for this work

Neurology

Research output: Chapter in Book/Report/Conference proceeding › Conference contribution

20 Scopus citations

Abstract

The question that started with the pioneering work of Otto Loewi in the 1920s, to identify how stimulation of the vagus nerve decreased heart rate, is approaching its 100th year anniversary. In the meantime, we have learned that the neurotransmitter acetylcholine acting through muscarinic M2 receptors activates cardiac potassium (Kir3) channels via the βγ subunits of G proteins, an important effect that contributes to slowing atrial pacemaker activity. Concurrent stimulation of M1 or M3 receptors hydrolyzes PIP₂, a signaling phospholipid essential to maintaining Kir3 channel activity, thus causing desensitization of channel activity and protecting the heart from overinhibition of pacemaker activity. Four mammalian members of the Kir3 subfamily, expressed in heart, brain, endocrine organs, etc., are modulated by a plethora of stimuli to regulate cellular excitability. With the recent great advances in ion channel structural biology, three-dimensional structures of Kir3 channels with PIP₂ and the Gβγ subunits are now available. Mechanistic insights have emerged that explain how modulatory control of activity feeds into a core mechanism of channel-PIP₂ interactions to regulate the conformation of channel gates. This complex but beautiful system continues to surprise us for almost 100 years with an apparent wisdom in its intricate design.

Original language	English (US)
Title of host publication	International Review of Neurobiology - Structure to Function of G Protein-Gated Inwardly Rectifying (GIRK) Channels, 2015
Editors	R. Adron Harris, Peter Jenner
Publisher	Academic Press Inc
Pages	1-26
Number of pages	26
ISBN (Print)	9780128024584
DOIs	https://doi.org/10.1016/bs.irn.2015.05.013
State	Published - 2015

Publication series

Name	International Review of Neurobiology
Volume	123
ISSN (Print)	0074-7742

Keywords

Computational model
Crystal structure
G proteins
G-loop gate
GIRK channels
Gβγ
Kir3 channels
PIP
Phosphatidylinositol bisphosphate
Phosphorylation

ASJC Scopus subject areas

Clinical Neurology
Cellular and Molecular Neuroscience

Access to Document

10.1016/bs.irn.2015.05.013

Cite this

Logothetis, D. E., Mahajan, R., Adney, S. K., Ha, J., Kawano, T., Meng, X. Y., & Cui, M. (2015). Unifying Mechanism of Controlling Kir3 Channel Activity by G Proteins and Phosphoinositides. In R. A. Harris, & P. Jenner (Eds.), International Review of Neurobiology - Structure to Function of G Protein-Gated Inwardly Rectifying (GIRK) Channels, 2015 (pp. 1-26). (International Review of Neurobiology; Vol. 123). Academic Press Inc. https://doi.org/10.1016/bs.irn.2015.05.013

Logothetis, Diomedes E. ; Mahajan, Rahul ; Adney, Scott K. et al. / Unifying Mechanism of Controlling Kir3 Channel Activity by G Proteins and Phosphoinositides. International Review of Neurobiology - Structure to Function of G Protein-Gated Inwardly Rectifying (GIRK) Channels, 2015. editor / R. Adron Harris ; Peter Jenner. Academic Press Inc, 2015. pp. 1-26 (International Review of Neurobiology).

@inproceedings{af9a24dd7236482e951c4e71e595ce34,

title = "Unifying Mechanism of Controlling Kir3 Channel Activity by G Proteins and Phosphoinositides",

abstract = "The question that started with the pioneering work of Otto Loewi in the 1920s, to identify how stimulation of the vagus nerve decreased heart rate, is approaching its 100th year anniversary. In the meantime, we have learned that the neurotransmitter acetylcholine acting through muscarinic M2 receptors activates cardiac potassium (Kir3) channels via the βγ subunits of G proteins, an important effect that contributes to slowing atrial pacemaker activity. Concurrent stimulation of M1 or M3 receptors hydrolyzes PIP2, a signaling phospholipid essential to maintaining Kir3 channel activity, thus causing desensitization of channel activity and protecting the heart from overinhibition of pacemaker activity. Four mammalian members of the Kir3 subfamily, expressed in heart, brain, endocrine organs, etc., are modulated by a plethora of stimuli to regulate cellular excitability. With the recent great advances in ion channel structural biology, three-dimensional structures of Kir3 channels with PIP2 and the Gβγ subunits are now available. Mechanistic insights have emerged that explain how modulatory control of activity feeds into a core mechanism of channel-PIP2 interactions to regulate the conformation of channel gates. This complex but beautiful system continues to surprise us for almost 100 years with an apparent wisdom in its intricate design.",

keywords = "Computational model, Crystal structure, G proteins, G-loop gate, GIRK channels, Gβγ, Kir3 channels, PIP, Phosphatidylinositol bisphosphate, Phosphorylation",

author = "Logothetis, {Diomedes E.} and Rahul Mahajan and Adney, {Scott K.} and Junghoon Ha and Takeharu Kawano and Meng, {Xuan Yu} and Meng Cui",

year = "2015",

doi = "10.1016/bs.irn.2015.05.013",

language = "English (US)",

isbn = "9780128024584",

series = "International Review of Neurobiology",

publisher = "Academic Press Inc",

pages = "1--26",

editor = "Harris, {R. Adron} and Peter Jenner",

booktitle = "International Review of Neurobiology - Structure to Function of G Protein-Gated Inwardly Rectifying (GIRK) Channels, 2015",

}

Logothetis, DE, Mahajan, R, Adney, SK, Ha, J, Kawano, T, Meng, XY & Cui, M 2015, Unifying Mechanism of Controlling Kir3 Channel Activity by G Proteins and Phosphoinositides. in RA Harris & P Jenner (eds), International Review of Neurobiology - Structure to Function of G Protein-Gated Inwardly Rectifying (GIRK) Channels, 2015. International Review of Neurobiology, vol. 123, Academic Press Inc, pp. 1-26. https://doi.org/10.1016/bs.irn.2015.05.013

Unifying Mechanism of Controlling Kir3 Channel Activity by G Proteins and Phosphoinositides. / Logothetis, Diomedes E.; Mahajan, Rahul; Adney, Scott K. et al.
International Review of Neurobiology - Structure to Function of G Protein-Gated Inwardly Rectifying (GIRK) Channels, 2015. ed. / R. Adron Harris; Peter Jenner. Academic Press Inc, 2015. p. 1-26 (International Review of Neurobiology; Vol. 123).

Research output: Chapter in Book/Report/Conference proceeding › Conference contribution

TY - GEN

T1 - Unifying Mechanism of Controlling Kir3 Channel Activity by G Proteins and Phosphoinositides

AU - Logothetis, Diomedes E.

AU - Mahajan, Rahul

AU - Adney, Scott K.

AU - Ha, Junghoon

AU - Kawano, Takeharu

AU - Meng, Xuan Yu

AU - Cui, Meng

PY - 2015

Y1 - 2015

N2 - The question that started with the pioneering work of Otto Loewi in the 1920s, to identify how stimulation of the vagus nerve decreased heart rate, is approaching its 100th year anniversary. In the meantime, we have learned that the neurotransmitter acetylcholine acting through muscarinic M2 receptors activates cardiac potassium (Kir3) channels via the βγ subunits of G proteins, an important effect that contributes to slowing atrial pacemaker activity. Concurrent stimulation of M1 or M3 receptors hydrolyzes PIP2, a signaling phospholipid essential to maintaining Kir3 channel activity, thus causing desensitization of channel activity and protecting the heart from overinhibition of pacemaker activity. Four mammalian members of the Kir3 subfamily, expressed in heart, brain, endocrine organs, etc., are modulated by a plethora of stimuli to regulate cellular excitability. With the recent great advances in ion channel structural biology, three-dimensional structures of Kir3 channels with PIP2 and the Gβγ subunits are now available. Mechanistic insights have emerged that explain how modulatory control of activity feeds into a core mechanism of channel-PIP2 interactions to regulate the conformation of channel gates. This complex but beautiful system continues to surprise us for almost 100 years with an apparent wisdom in its intricate design.

AB - The question that started with the pioneering work of Otto Loewi in the 1920s, to identify how stimulation of the vagus nerve decreased heart rate, is approaching its 100th year anniversary. In the meantime, we have learned that the neurotransmitter acetylcholine acting through muscarinic M2 receptors activates cardiac potassium (Kir3) channels via the βγ subunits of G proteins, an important effect that contributes to slowing atrial pacemaker activity. Concurrent stimulation of M1 or M3 receptors hydrolyzes PIP2, a signaling phospholipid essential to maintaining Kir3 channel activity, thus causing desensitization of channel activity and protecting the heart from overinhibition of pacemaker activity. Four mammalian members of the Kir3 subfamily, expressed in heart, brain, endocrine organs, etc., are modulated by a plethora of stimuli to regulate cellular excitability. With the recent great advances in ion channel structural biology, three-dimensional structures of Kir3 channels with PIP2 and the Gβγ subunits are now available. Mechanistic insights have emerged that explain how modulatory control of activity feeds into a core mechanism of channel-PIP2 interactions to regulate the conformation of channel gates. This complex but beautiful system continues to surprise us for almost 100 years with an apparent wisdom in its intricate design.

KW - Computational model

KW - Crystal structure

KW - G proteins

KW - G-loop gate

KW - GIRK channels

KW - Gβγ

KW - Kir3 channels

KW - PIP

KW - Phosphatidylinositol bisphosphate

KW - Phosphorylation

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DO - 10.1016/bs.irn.2015.05.013

M3 - Conference contribution

C2 - 26422981

AN - SCOPUS:84947489016

SN - 9780128024584

T3 - International Review of Neurobiology

SP - 1

EP - 26

BT - International Review of Neurobiology - Structure to Function of G Protein-Gated Inwardly Rectifying (GIRK) Channels, 2015

A2 - Harris, R. Adron

A2 - Jenner, Peter

PB - Academic Press Inc

ER -

Logothetis DE, Mahajan R, Adney SK, Ha J, Kawano T, Meng XY et al. Unifying Mechanism of Controlling Kir3 Channel Activity by G Proteins and Phosphoinositides. In Harris RA, Jenner P, editors, International Review of Neurobiology - Structure to Function of G Protein-Gated Inwardly Rectifying (GIRK) Channels, 2015. Academic Press Inc. 2015. p. 1-26. (International Review of Neurobiology). doi: 10.1016/bs.irn.2015.05.013

Unifying Mechanism of Controlling Kir3 Channel Activity by G Proteins and Phosphoinositides

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