Therapeutic Potential of Metabotropic GABA (GABAB) Receptors and their Effector Ion Channels

SK, HCN, and M channels are medium afterhyperpolarization (mAHP)-mediating ion channels. The three channels co-express in various brain regions, and their collective action strongly influences cellular excitability. However, significant diversity exists in the expression of channel isoforms in distinct brain regions and various subcellular compartments, which contributes to an equally diverse set of specific neuronal functions. The current review emphasizes the collective behavior of the three classes of mAHP channels and discusses how these channels function together although they play specialized roles. We discuss the biophysical properties of these channels, signaling pathways that influence the activity of the three mAHP channels, various chemical modulators that alter channel activity and their therapeutic potential in treating various neurological anomalies. Additionally, we discuss the role of mAHP channels in the pathophysiology of various neurological diseases and how their modulation can alleviate some of the symptoms.

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Monoclonal Antibodies Targeting Ion Channels and Their Therapeutic Potential

Frontiers in Pharmacology ◽

10.3389/fphar.2019.00606 ◽

2019 ◽

Vol 10 ◽

Cited By ~ 5

Author(s):

Aurélien Haustrate ◽

Aline Hantute-Ghesquier ◽

Natalia Prevarskaya ◽

V’yacheslav Lehen’kyi

Keyword(s):

Monoclonal Antibodies ◽

Ion Channels ◽

Therapeutic Potential

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Atomistic Insights of Calmodulin Gating of Complete Ion Channels

International Journal of Molecular Sciences ◽

10.3390/ijms21041285 ◽

2020 ◽

Vol 21 (4) ◽

pp. 1285 ◽

Cited By ~ 5

Author(s):

Eider Núñez ◽

Arantza Muguruza-Montero ◽

Alvaro Villarroel

Keyword(s):

Membrane Potential ◽

Ion Channels ◽

Therapeutic Potential ◽

Structural Information ◽

Lipid Binding ◽

Channel Structure ◽

Extracellular Medium ◽

Alpha Helices ◽

Functional Studies ◽

Direct Binding

Intracellular calcium is essential for many physiological processes, from neuronal signaling and exocytosis to muscle contraction and bone formation. Ca2+ signaling from the extracellular medium depends both on membrane potential, especially controlled by ion channels selective to K+, and direct permeation of this cation through specialized channels. Calmodulin (CaM), through direct binding to these proteins, participates in setting the membrane potential and the overall permeability to Ca2+. Over the past years many structures of complete channels in complex with CaM at near atomic resolution have been resolved. In combination with mutagenesis-function, structural information of individual domains and functional studies, different mechanisms employed by CaM to control channel gating are starting to be understood at atomic detail. Here, new insights regarding four types of tetrameric channels with six transmembrane (6TM) architecture, Eag1, SK2/SK4, TRPV5/TRPV6 and KCNQ1–5, and its regulation by CaM are described structurally. Different CaM regions, N-lobe, C-lobe and EF3/EF4-linker play prominent signaling roles in different complexes, emerging the realization of crucial non-canonical interactions between CaM and its target that are only evidenced in the full-channel structure. Different mechanisms to control gating are used, including direct and indirect mechanical actuation over the pore, allosteric control, indirect effect through lipid binding, as well as direct plugging of the pore. Although each CaM lobe engages through apparently similar alpha-helices, they do so using different docking strategies. We discuss how this allows selective action of drugs with great therapeutic potential.

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CRMP2 and voltage-gated ion channels: potential roles in neuropathic pain

Neuronal Signaling ◽

10.1042/ns20170220 ◽

2018 ◽

Vol 2 (1) ◽

Cited By ~ 19

Author(s):

Lindsey A. Chew ◽

Rajesh Khanna

Keyword(s):

Neuropathic Pain ◽

Ion Channels ◽

Therapeutic Potential ◽

Channel Trafficking ◽

Voltage Gated ◽

High Profile ◽

Mediator Protein ◽

Voltage Gated Ion Channels ◽

Ion Channel Trafficking ◽

Gated Ion Channels

Neuropathic pain represents a significant and mounting burden on patients and society at large. Management of neuropathic pain, however, is both intricate and challenging, exacerbated by the limited quantity and quality of clinically available treatments. On this stage, dysfunctional voltage-gated ion channels, especially the presynaptic N-type voltage-gated calcium channel (VGCC) (Cav2.2) and the tetrodotoxin-sensitive voltage-gated sodium channel (VGSC) (Nav1.7), underlie the pathophysiology of neuropathic pain and serve as high profile therapeutic targets. Indirect regulation of these channels holds promise for the treatment of neuropathic pain. In this review, we focus on collapsin response mediator protein 2 (CRMP2), a protein with emergent roles in voltage-gated ion channel trafficking and discuss the therapeutic potential of targetting this protein.

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Ion channels in cancer: future perspectives and clinical potential

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2013.0108 ◽

2014 ◽

Vol 369 (1638) ◽

pp. 20130108 ◽

Cited By ~ 72

Author(s):

Florian Lang ◽

Christos Stournaras

Keyword(s):

Ion Channels ◽

Cell Survival ◽

Tumour Cell ◽

Tumour Growth ◽

Therapeutic Potential ◽

Short Review ◽

Therapy Resistance ◽

Tumour Cells ◽

Anion Channels

Ion transport across the cell membrane mediated by channels and carriers participate in the regulation of tumour cell survival, death and motility. Moreover, the altered regulation of channels and carriers is part of neoplastic transformation. Experimental modification of channel and transporter activity impacts tumour cell survival, proliferation, malignant progression, invasive behaviour or therapy resistance of tumour cells. A wide variety of distinct Ca 2+ permeable channels, K + channels, Na + channels and anion channels have been implicated in tumour growth and metastasis. Further experimental information is, however, needed to define the specific role of individual channel isoforms critically important for malignancy. Compelling experimental evidence supports the assumption that the pharmacological inhibition of ion channels or their regulators may be attractive targets to counteract tumour growth, prevent metastasis and overcome therapy resistance of tumour cells. This short review discusses the role of Ca 2+ permeable channels, K + channels, Na + channels and anion channels in tumour growth and metastasis and the therapeutic potential of respective inhibitors.

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Contributions of Bile Acids to Gastrointestinal Physiology as Receptor Agonists and Modifiers of Ion Channels

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00125.2021 ◽

2021 ◽

Author(s):

Stephen Joseph Keely ◽

Andreacarola Urso ◽

Alexandr V Ilyaskin ◽

Christoph Korbmacher ◽

Nigel W Bunnett ◽

...

Keyword(s):

Ion Channels ◽

Bile Acids ◽

Intestinal Motility ◽

Molecular Mechanisms ◽

Epithelial Transport ◽

Therapeutic Potential ◽

Gastrointestinal Diseases ◽

Gastrointestinal Physiology ◽

The Past ◽

Current Review

BAs are known to be important regulators of intestinal motility and epithelial fluid and electrolyte transport. Over the past two decades, significant advances in identifying and characterizing the receptors, transporters, and ion channels targeted by bile acids (BAs) has led to exciting new insights into the molecular mechanisms involved in these processes. Our appreciation of BAs, their receptors and BA-modulated ion channels as potential targets for the development of new approaches to treat intestinal motility and transport disorders is increasing. In the current review, we aim to summarize recent advances in our knowledge of the different BA receptors and BA-modulated ion channels present in the gastrointestinal system. We discuss how they regulate motility and epithelial transport, their roles in pathogenesis and their therapeutic potential in a range of gastrointestinal diseases.

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