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Article ; Online: Chronic intermittent hypoxia elicits distinct transcriptomic responses among neurons and oligodendrocytes within the brainstem of mice.

Bhagavan, Hemalatha / Wei, Aguan D / Oliveira, Luiz M / Aldinger, Kimberly A / Ramirez, Jan-Marino

American journal of physiology. Lung cellular and molecular physiology

2024

Abstract: Chronic intermittent hypoxia (CIH) is a prevalent condition characterized by recurrent episodes of oxygen deprivation, linked to respiratory and neurological disorders. Prolonged CIH is known to have adverse effects, including endothelial dysfunction, ... ...

Abstract	Chronic intermittent hypoxia (CIH) is a prevalent condition characterized by recurrent episodes of oxygen deprivation, linked to respiratory and neurological disorders. Prolonged CIH is known to have adverse effects, including endothelial dysfunction, chronic inflammation, oxidative stress, and impaired neuronal function. These factors can contribute to serious comorbidities, including metabolic disorders and cardiovascular diseases. To investigate the molecular impact of CIH, we examined male C57BL/6J mice exposed to CIH for 21 days, comparing to normoxic controls. We employed single-nucleus RNA sequencing to comprehensively examine the transcriptomic impact of CIH on key cell classes within the brainstem, specifically excitatory neurons, inhibitory neurons, and oligodendrocytes. These cell classes regulate essential physiological functions, including autonomic tone, cardiovascular control, and respiration. Through analysis of 10,995 nuclei isolated from pontine-medullary tissue, we identified seven major cell classes, further subdivided into 24 clusters. Our findings among these cell classes, revealed significant differential gene expression, underscoring their distinct responses to CIH. Notably, neurons exhibited transcriptional dysregulation of genes associated with synaptic transmission, and structural remodeling. In addition, we find dysregulated genes encoding ion channels, and inflammatory response. Concurrently, oligodendrocytes exhibited dysregulated genes associated with oxidative phosphorylation and oxidative stress. Utilizing CellChat network analysis, we uncovered CIH-dependent altered patterns of diffusible inter-cellular signaling. These insights offer a comprehensive transcriptomic cellular atlas of the pons-medulla and provide a fundamental resource for the analysis of molecular adaptations triggered by CIH.
Language	English
Publishing date	2024-04-09
Publishing country	United States
Document type	Journal Article
ZDB-ID	1013184-x
ISSN	1522-1504 ; 1040-0605
ISSN (online)	1522-1504
ISSN	1040-0605
DOI	10.1152/ajplung.00320.2023
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Article: Presynaptic Mechanisms and KCNQ Potassium Channels Modulate Opioid Depression of Respiratory Drive.

Wei, Aguan D / Ramirez, Jan-Marino

Frontiers in physiology

2019 Volume 10, Page(s) 1407

Abstract: Opioid-induced respiratory depression (OIRD) is the major cause of death associated with opioid analgesics and drugs of abuse, but the underlying cellular and molecular mechanisms remain poorly understood. We investigated opioid ... ...

Abstract	Opioid-induced respiratory depression (OIRD) is the major cause of death associated with opioid analgesics and drugs of abuse, but the underlying cellular and molecular mechanisms remain poorly understood. We investigated opioid action
Language	English
Publishing date	2019-11-22
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2564217-0
ISSN	1664-042X
ISSN	1664-042X
DOI	10.3389/fphys.2019.01407
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Article ; Online: Cold acclimation via the KQT-2 potassium channel is modulated by oxygen in

Okahata, Misaki / Wei, Aguan D / Ohta, Akane / Kuhara, Atsushi

Science advances

2019 Volume 5, Issue 2, Page(s) eaav3631

Abstract: Adaptive responses to external temperatures are essential for survival in changing environments. We show here that environmental oxygen concentration affects cold acclimation ... ...

Abstract	Adaptive responses to external temperatures are essential for survival in changing environments. We show here that environmental oxygen concentration affects cold acclimation in
MeSH term(s)	Acclimatization ; Animals ; Caenorhabditis elegans/physiology ; Cold Temperature ; Gene Expression ; KCNQ2 Potassium Channel/genetics ; KCNQ2 Potassium Channel/metabolism ; Models, Biological ; Mutation ; Oxygen/metabolism ; Sensory Receptor Cells/metabolism
Chemical Substances	KCNQ2 Potassium Channel ; Oxygen (S88TT14065)
Language	English
Publishing date	2019-02-06
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2810933-8
ISSN	2375-2548 ; 2375-2548
ISSN (online)	2375-2548
ISSN	2375-2548
DOI	10.1126/sciadv.aav3631
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Article: AAV-mediated interneuron-specific gene replacement for Dravet syndrome.

Mich, John K / Ryu, Jiyun / Wei, Aguan D / Gore, Bryan B / Guo, Rong / Bard, Angela M / Martinez, Refugio A / Bishaw, Yemeserach / Luber, Em / Oliveira Santos, Luiz M / Miranda, Nicole / Ramirez, Jan-Marino / Ting, Jonathan T / Lein, Ed S / Levi, Boaz P / Kalume, Franck K

bioRxiv : the preprint server for biology

2023

Abstract: Dravet syndrome (DS) is a devastating developmental epileptic encephalopathy marked by treatment-resistant seizures, developmental delay, intellectual disability, motor deficits, and a 10-20% rate of premature death. Most DS patients harbor loss-of- ... ...

Abstract	Dravet syndrome (DS) is a devastating developmental epileptic encephalopathy marked by treatment-resistant seizures, developmental delay, intellectual disability, motor deficits, and a 10-20% rate of premature death. Most DS patients harbor loss-of-function mutations in one copy of
Language	English
Publishing date	2023-12-15
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.12.15.571820
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Article ; Online: Neuronal mechanisms underlying opioid-induced respiratory depression: our current understanding.

Ramirez, Jan-Marino / Burgraff, Nicholas J / Wei, Aguan D / Baertsch, Nathan A / Varga, Adrienn G / Baghdoyan, Helen A / Lydic, Ralph / Morris, Kendall F / Bolser, Donald C / Levitt, Erica S

Journal of neurophysiology

2021 Volume 125, Issue 5, Page(s) 1899–1919

Abstract: Opioid-induced respiratory depression (OIRD) represents the primary cause of death associated with therapeutic and recreational opioid use. Within the United States, the rate of death from opioid abuse since the early 1990s has grown disproportionally, ... ...

Abstract	Opioid-induced respiratory depression (OIRD) represents the primary cause of death associated with therapeutic and recreational opioid use. Within the United States, the rate of death from opioid abuse since the early 1990s has grown disproportionally, prompting the classification as a nationwide "epidemic." Since this time, we have begun to unravel many fundamental cellular and systems-level mechanisms associated with opioid-related death. However, factors such as individual vulnerability, neuromodulatory compensation, and redundancy of opioid effects across central and peripheral nervous systems have created a barrier to a concise, integrative view of OIRD. Within this review, we bring together multiple perspectives in the field of OIRD to create an overarching viewpoint of what we know, and where we view this essential topic of research going forward into the future.
MeSH term(s)	Analgesics, Opioid/adverse effects ; Analgesics, Opioid/pharmacology ; Animals ; Central Pattern Generators/drug effects ; Humans ; Medulla Oblongata/drug effects ; Opioid-Related Disorders/complications ; Respiratory Insufficiency/chemically induced
Chemical Substances	Analgesics, Opioid
Language	English
Publishing date	2021-04-07
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	80161-6
ISSN	1522-1598 ; 0022-3077
ISSN (online)	1522-1598
ISSN	0022-3077
DOI	10.1152/jn.00017.2021
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Article ; Online: Human

Wei, Aguan D / Wakenight, Paul / Zwingman, Theresa A / Bard, Angela M / Sahai, Nikhil / Willemsen, Marjolein H / Schelhaas, Helenius J / Stegmann, Alexander P A / Verhoeven, Judith S / de Man, Stella A / Wessels, Marja W / Kleefstra, Tjitske / Shinde, Deepali N / Helbig, Katherine L / Basinger, Alice / Wagner, Victoria F / Rodriguez-Buritica, David / Bryant, Emily / Millichap, John J /

Millen, Kathleen J / Dobyns, William B / Ramirez, Jan-Marino / Kalume, Franck K

Journal of neurophysiology

2022 Volume 128, Issue 1, Page(s) 40–61

Abstract: We identified six novel de novo ... ...

Abstract	We identified six novel de novo human
MeSH term(s)	Animals ; Child ; Cricetinae ; Cricetulus ; Epilepsy/genetics ; HEK293 Cells ; Humans ; Intellectual Disability/genetics ; KCNQ Potassium Channels ; Mice ; Mutation, Missense ; Seizures
Chemical Substances	KCNQ Potassium Channels ; KCNQ5 protein, human
Language	English
Publishing date	2022-05-18
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	80161-6
ISSN	1522-1598 ; 0022-3077
ISSN (online)	1522-1598
ISSN	0022-3077
DOI	10.1152/jn.00509.2021
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Article ; Online: International Union of Basic and Clinical Pharmacology. C. Nomenclature and Properties of Calcium-Activated and Sodium-Activated Potassium Channels.

Kaczmarek, Leonard K / Aldrich, Richard W / Chandy, K George / Grissmer, Stephan / Wei, Aguan D / Wulff, Heike

Pharmacological reviews

2016 Volume 69, Issue 1, Page(s) 1–11

Abstract: A subset of potassium channels is regulated primarily by changes in the cytoplasmic concentration of ions, including calcium, sodium, chloride, and protons. The eight members of this subfamily were originally all designated as calcium-activated channels. ...

Abstract	A subset of potassium channels is regulated primarily by changes in the cytoplasmic concentration of ions, including calcium, sodium, chloride, and protons. The eight members of this subfamily were originally all designated as calcium-activated channels. More recent studies have clarified the gating mechanisms for these channels and have documented that not all members are sensitive to calcium. This article describes the molecular relationships between these channels and provides an introduction to their functional properties. It also introduces a new nomenclature that differentiates between calcium- and sodium-activated potassium channels.
MeSH term(s)	Animals ; Calcium/metabolism ; Chlorides/metabolism ; Humans ; Intermediate-Conductance Calcium-Activated Potassium Channels/classification ; Intermediate-Conductance Calcium-Activated Potassium Channels/metabolism ; Ion Channel Gating ; Large-Conductance Calcium-Activated Potassium Channel alpha Subunits/classification ; Large-Conductance Calcium-Activated Potassium Channel alpha Subunits/metabolism ; Male ; Potassium Channels/classification ; Potassium Channels/metabolism ; Potassium Channels, Calcium-Activated/classification ; Potassium Channels, Calcium-Activated/metabolism ; Sodium/metabolism ; Spermatozoa/metabolism ; Terminology as Topic
Chemical Substances	Chlorides ; Intermediate-Conductance Calcium-Activated Potassium Channels ; KCNMA1 protein, human ; KCNN4 protein, human ; Large-Conductance Calcium-Activated Potassium Channel alpha Subunits ; Potassium Channels ; Potassium Channels, Calcium-Activated ; Sodium (9NEZ333N27) ; Calcium (SY7Q814VUP)
Language	English
Publishing date	2016-11-15
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	209898-2
ISSN	1521-0081 ; 0031-6997
ISSN (online)	1521-0081
ISSN	0031-6997
DOI	10.1124/pr.116.012864
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Article ; Online: A novel excitatory network for the control of breathing.

Anderson, Tatiana M / Garcia, Alfredo J / Baertsch, Nathan A / Pollak, Julia / Bloom, Jacob C / Wei, Aguan D / Rai, Karan G / Ramirez, Jan-Marino

Nature

2016 Volume 536, Issue 7614, Page(s) 76–80

Abstract: Breathing must be tightly coordinated with other behaviours such as vocalization, swallowing, and coughing. These behaviours occur after inspiration, during a respiratory phase termed postinspiration. Failure to coordinate postinspiration with ... ...

Abstract	Breathing must be tightly coordinated with other behaviours such as vocalization, swallowing, and coughing. These behaviours occur after inspiration, during a respiratory phase termed postinspiration. Failure to coordinate postinspiration with inspiration can result in aspiration pneumonia, the leading cause of death in Alzheimer's disease, Parkinson's disease, dementia, and other neurodegenerative diseases. Here we describe an excitatory network that generates the neuronal correlate of postinspiratory activity in mice. Glutamatergic-cholinergic neurons form the basis of this network, and GABA (γ-aminobutyric acid)-mediated inhibition establishes the timing and coordination relative to inspiration. We refer to this network as the postinspiratory complex (PiCo). The PiCo has autonomous rhythm-generating properties and is necessary and sufficient for postinspiratory activity in vivo.The PiCo also shows distinct responses to neuromodulators when compared to other excitatory brainstem networks. On the basis of the discovery of the PiCo, we propose that each of the three phases of breathing is generated by a distinct excitatory network: the pre-Bötzinger complex, which has been linked to inspiration; the PiCo, as described here for the neuronal control of postinspiration; and the lateral parafacial region (pF(L)), which has been associated with active expiration, a respiratory phase that is recruited during high metabolic demand.
MeSH term(s)	Animals ; Cholinergic Neurons/metabolism ; Female ; Glutamine/metabolism ; Male ; Mice ; Neural Inhibition/physiology ; Neural Pathways/cytology ; Neural Pathways/physiology ; Respiration ; Respiratory Center/anatomy & histology ; Respiratory Center/cytology ; Respiratory Center/physiology ; Synapses/metabolism ; Time Factors ; gamma-Aminobutyric Acid/metabolism
Chemical Substances	Glutamine (0RH81L854J) ; gamma-Aminobutyric Acid (56-12-2)
Language	English
Publishing date	2016--04
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	120714-3
ISSN	1476-4687 ; 0028-0836
ISSN (online)	1476-4687
ISSN	0028-0836
DOI	10.1038/nature18944
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Article ; Online: The Concise Guide to PHARMACOLOGY 2023/24: Ion channels.

Alexander, Stephen P H / Mathie, Alistair A / Peters, John A / Veale, Emma L / Striessnig, Jörg / Kelly, Eamonn / Armstrong, Jane F / Faccenda, Elena / Harding, Simon D / Davies, Jamie A / Aldrich, Richard W / Attali, Bernard / Baggetta, Austin M / Becirovic, Elvir / Biel, Martin / Bill, Roslyn M / Caceres, Ana I / Catterall, William A / Conner, Alex C /

Davies, Paul / De Clerq, Katrien / Delling, Markus / Di Virgilio, Francesco / Falzoni, Simonetta / Fenske, Stefanie / Fortuny-Gomez, Anna / Fountain, Samuel / George, Chandy / Goldstein, Steve A N / Grimm, Christian / Grissmer, Stephan / Ha, Kotdaji / Hammelmann, Verena / Hanukoglu, Israel / Hu, Meiqin / Ijzerman, Ad P / Jabba, Sairam V / Jarvis, Mike / Jensen, Anders A / Jordt, Sven E / Kaczmarek, Leonard K / Kellenberger, Stephan / Kennedy, Charles / King, Brian / Kitchen, Philip / Liu, Qiang / Lynch, Joseph W / Meades, Jessica / Mehlfeld, Verena / Nicke, Annette / Offermanns, Stefan / Perez-Reyes, Edward / Plant, Leigh D / Rash, Lachlan / Ren, Dejian / Salman, Mootaz M / Sieghart, Werner / Sivilotti, Lucia G / Smart, Trevor G / Snutch, Terrance P / Tian, Jinbin / Trimmer, James S / Van den Eynde, Charlotte / Vriens, Joris / Wei, Aguan D / Winn, Brenda T / Wulff, Heike / Xu, Haoxing / Yang, Fan / Fang, Wei / Yue, Lixia / Zhang, Xiaoli / Zhu, Michael

British journal of pharmacology

2023 Volume 180 Suppl 2, Page(s) S145–S222

Abstract: The Concise Guide to PHARMACOLOGY 2023/24 is the sixth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of approximately 1800 drug targets, and over 6000 interactions ... ...

Abstract	The Concise Guide to PHARMACOLOGY 2023/24 is the sixth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of approximately 1800 drug targets, and over 6000 interactions with about 3900 ligands. There is an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (https://www.guidetopharmacology.org/), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes almost 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.16178. Ion channels are one of the six major pharmacological targets into which the Guide is divided, with the others being: G protein-coupled receptors, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2023, and supersedes data presented in the 2021/22, 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.
MeSH term(s)	Humans ; Databases, Pharmaceutical ; Ion Channels/chemistry ; Ligands ; Receptors, G-Protein-Coupled ; Databases, Factual ; Pharmacology
Chemical Substances	Ion Channels ; Ligands ; Receptors, G-Protein-Coupled
Language	English
Publishing date	2023-12-21
Publishing country	England
Document type	Journal Article
ZDB-ID	80081-8
ISSN	1476-5381 ; 0007-1188
ISSN (online)	1476-5381
ISSN	0007-1188
DOI	10.1111/bph.16178
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Article ; Online: Medial habenula output circuit mediated by α5 nicotinic receptor-expressing GABAergic neurons in the interpeduncular nucleus.

Hsu, Yun-Wei A / Tempest, Lynne / Quina, Lely A / Wei, Aguan D / Zeng, Hongkui / Turner, Eric E

The Journal of neuroscience : the official journal of the Society for Neuroscience

2013 Volume 33, Issue 46, Page(s) 18022–18035

Abstract: The Chrna5 gene encodes the α5 nicotinic acetylcholine receptor subunit, an "accessory" subunit of pentameric nicotinic receptors, that has been shown to play a role in nicotine-related behaviors in rodents and is genetically linked to smoking behavior ... ...

Abstract	The Chrna5 gene encodes the α5 nicotinic acetylcholine receptor subunit, an "accessory" subunit of pentameric nicotinic receptors, that has been shown to play a role in nicotine-related behaviors in rodents and is genetically linked to smoking behavior in humans. Here we have used a BAC transgenic mouse line, α5(GFP), to examine the cellular phenotype, connectivity, and function of α5-expressing neurons. Although the medial habenula (MHb) has been proposed as a site of α5 function, α5(GFP) is not detectable in the MHb, and α5 mRNA is expressed there only at very low levels. However, α5(GFP) is strongly expressed in a subset of neurons in the interpeduncular nucleus (IP), median raphe/paramedian raphe (MnR/PMnR), and dorsal tegmental area (DTg). Double-label fluorescence in situ hybridization reveals that these neurons are exclusively GABAergic. Transgenic and conventional tract tracing show that α5(GFP) neurons in the IP project principally to the MnR/PMnR and DTg/interfascicular dorsal raphe, both areas rich in serotonergic neurons. The α5(GFP) neurons in the IP are located in a region that receives cholinergic fiber inputs from the ventral MHb, and optogenetically assisted circuit mapping demonstrates a monosynaptic connection between these cholinergic neurons and α5(GFP) IP neurons. Selective inhibitors of both α4β2- and α3β4-containing nicotinic receptors were able to reduce nicotine-evoked inward currents in α5(GFP) neurons in the IP, suggesting a mixed nicotinic receptor profile in these cells. Together, these findings show that the α5-GABAergic interneurons form a link from the MHb to serotonergic brain centers, which is likely to mediate some of the behavioral effects of nicotine.
MeSH term(s)	Animals ; Female ; GABAergic Neurons/metabolism ; Gene Expression Regulation ; Habenula/physiology ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Nerve Net/physiology ; Organ Culture Techniques ; Receptors, GABA-A/biosynthesis ; Serotonergic Neurons/metabolism
Chemical Substances	Gabra5 protein, mouse ; Receptors, GABA-A
Language	English
Publishing date	2013-11-13
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	604637-x
ISSN	1529-2401 ; 0270-6474
ISSN (online)	1529-2401
ISSN	0270-6474
DOI	10.1523/JNEUROSCI.2927-13.2013
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