Michael W. Pennington

article

K_V1.3 channels are novel determinants of macrophage‐dependent endothelial dysfunction in angiotensin II‐induced hypertension in mice

Miguel A. Olivencia, Marta Martínez‐Casales, Diego A. Peraza, Ana B. García‐Redondo, more

British Journal of Pharmacology > 178 > 8 > 1836 - 1854

Background and Purpose K_V1.3 channels are expressed in vascular smooth muscle cells (VSMCs), where they contribute to proliferation rather than contraction and participate in vascular remodelling. K_V1.3 channels are also expressed in macrophages, where they assemble with K_V1.5 channels (K_V1.3/K_V1.5), whose activation generates a K_V current. In macrophages, the K_V1.3/K_V1.5 ratio is increased by classical...

article

Biophysical basis for Kv1.3 regulation of membrane potential changes induced by P2X4‐mediated calcium entry in microglia

Hai M. Nguyen, Jacopo Lucente, Yi‐Je Chen, Yanjun Cui, more

Glia > 68 > 11 > 2377 - 2394

Microglia‐mediated inflammation exerts adverse effects in ischemic stroke and in neurodegenerative disorders such as Alzheimer's disease (AD). Expression of the voltage‐gated potassium channel Kv1.3 is required for microglia activation. Both genetic deletion and pharmacological inhibition of Kv1.3 are effective in reducing microglia activation and the associated inflammatory responses, as well as...

article

KCa1.1 and Kv1.3 channels regulate the interactions between fibroblast-like synoviocytes and T lymphocytes during rheumatoid arthritis

Mark R. Tanner, Michael W. Pennington, Satendra S. Chauhan, Teresina Laragione, more

Arthritis Research & Therapy > 2019 > 21 > 1 > 1-21

Background Fibroblast-like synoviocytes (FLS) and CCR7⁻ effector memory T (T_EM) cells are two of the major cell types implicated in the progression of rheumatoid arthritis (RA). In particular, FLS become highly invasive, whereas T_EM cells proliferate and secrete proinflammatory cytokines, during RA. FLS and T cells may also interact and influence each other’s phenotypes. Inhibition of the pathogenic...

article

Synthesis, folding, structure and activity of a predicted peptide from the sea anemone Oulactis sp. with an ShKT fold

Bankala Krishnarjuna, Jessica Villegas-Moreno, Michela L. Mitchell, Agota Csoti, more

Toxicon > 2018 > 150 > C > 50-59

Sea anemone venom is rich in bioactive compounds, including peptides containing multiple disulfide bridges. In a transcriptomic study on Oulactis sp., we identified the putative 36-residue peptide, OspTx2b, which is an isoform of the K_V channel blocker OspTx2a (Sunanda P et al. [2018] Identification, chemical synthesis, structure and function of a new K_V1 channel blocking peptide from Oulactis sp...

article

Targeting potassium channels in rheumatoid arthritis

Mark R. Tanner, Redwan Huq, Rajeev Tajhya, Michael W. Pennington, more

Toxicon > 2018 > 149 > C > 86

article

Identification and therapeutic modulation of a pro-inflammatory subset of disease-associated-microglia in Alzheimer’s disease

Srikant Rangaraju, Eric B. Dammer, Syed Ali Raza, Priyadharshini Rathakrishnan, more

Molecular Neurodegeneration > 2018 > 13 > 1 > 1-25

Background Disease-associated-microglia (DAM) represent transcriptionally-distinct and neurodegeneration-specific microglial profiles with unclear significance in Alzheimer’s disease (AD). An understanding of heterogeneity within DAM and their key regulators may guide pre-clinical experimentation and drug discovery. Methods Weighted co-expression network analysis (WGCNA) was applied to existing...

article

Structure, folding and stability of a minimal homologue from Anemonia sulcata of the sea anemone potassium channel blocker ShK

Bankala Krishnarjuna, Christopher A. MacRaild, Punnepalli Sunanda, Rodrigo A.V. Morales, more

Peptides > 2018 > 99 > C > 169-178

Peptide toxins elaborated by sea anemones target various ion-channel sub-types. Recent transcriptomic studies of sea anemones have identified several novel candidate peptides, some of which have cysteine frameworks identical to those of previously reported sequences. One such peptide is AsK132958, which was identified in a transcriptomic study of Anemonia sulcata and has a cysteine framework similar...

article

Enantioselective synthesis of Fmoc-l-3-(2-benzothienyl)alanine (2-BtAla) via diastereoselective alkylation of a glycine equivalent

Satendra S. Chauhan, Suisheng Shang, Michael W. Pennington

Tetrahedron Letters > 2017 > 58 > 46 > 4388-4390

Stereoselective alkylation of the anion derived from (2R)-2,5-dihydro-3,6-dimethoxy-2-isopropylpyrazine with 2-chloromethylbenzothiophene afforded the corresponding trans-monosubstituted product, (2S,5R)-2-((1-benzo[b]thiophen-2-yl)methyl)-3,6-dimethoxy-5-(propan-2-yl)-2,5-dihyropyrazine in 88% yield. Hydrolysis of the alkylated product using 40% TFA/H₂O at 0 °C and subsequent protection of the α-amino...

article

Prolonged immunomodulation in inflammatory arthritis using the selective Kv1.3 channel blocker HsTX1[R14A] and its PEGylated analog

Mark R. Tanner, Rajeev B. Tajhya, Redwan Huq, Elizabeth J. Gehrmann, more

Clinical Immunology > 2017 > 180 > C > 45-57

Effector memory T lymphocytes (T_EM cells) that lack expression of CCR7 are major drivers of inflammation in a number of autoimmune diseases, including multiple sclerosis and rheumatoid arthritis. The Kv1.3 potassium channel is a key regulator of CCR7⁻ T_EM cell activation. Blocking Kv1.3 inhibits T_EM cell activation and attenuates inflammation in autoimmunity, and as such, Kv1.3 has emerged as a promising...

article

A systems pharmacology-based approach to identify novel Kv1.3 channel-dependent mechanisms in microglial activation

Srikant Rangaraju, Syed Ali Raza, Andrea Pennati, Qiudong Deng, more

Journal of Neuroinflammation > 2017 > 14 > 1 > 1-20

Background Kv1.3 potassium channels regulate microglial functions and are overexpressed in neuroinflammatory diseases. Kv1.3 blockade may selectively inhibit pro-inflammatory microglia in neurological diseases but the molecular and cellular mechanisms regulated by Kv1.3 channels are poorly defined. Methods We performed immunoblotting and flow cytometry to confirm Kv1.3 channel upregulation in lipopolysaccharide...

chapter

Efficient Synthesis of Protected L-Phosphonophenylalanine (Ppa) Derivatives Suitable for Solid Phase Synthesis

Satendra S. Chauhan, A. Varshney, B. Verma, Michael W. Pennington

Advances in Experimental Medicine and Biology > Peptides for Youth > Peptide, Protein, and Peptidomimetic Synthesis honoring Ralph Hirschmann > 191-192

article

N‐terminally extended analogues of the K⁺ channel toxin from Stichodactyla helianthus as potent and selective blockers of the voltage‐gated potassium channel Kv1.3

Shih C. Chang, Redwan Huq, Sandeep Chhabra, Christine Beeton, more

The FEBS Journal > 282 > 12 > 2247 - 2259

The voltage‐gated potassium channel Kv1.3 is an important target for the treatment of autoimmune diseases and asthma. Blockade of Kv1.3 by the sea anemone peptide K⁺‐channel toxin from Stichodactyla helianthus (ShK) inhibits the proliferation of effector memory T lymphocytes and ameliorates autoimmune diseases in animal models. However, the lack of selectivity of ShK for Kv1.3 over the Kv1.1 subtype...

article

Buccal mucosal delivery of a potent peptide leads to therapeutically-relevant plasma concentrations for the treatment of autoimmune diseases

Liang Jin, Ben J. Boyd, Paul J. White, Michael W. Pennington, more

Journal of Controlled Release > 2015 > 199 > C > 37-44

Stichodactyla helianthus neurotoxin (ShK) is an immunomodulatory peptide currently under development for the treatment of autoimmune diseases, including multiple sclerosis and rheumatoid arthritis by parenteral administration. To overcome the low patient compliance of conventional self-injections, we have investigated the potential of the buccal mucosa as an alternative delivery route for ShK both...

article

Total Synthesis of Human Hepcidin through Regioselective Disulfide‐Bond Formation by using the Safety‐Catch Cysteine Protecting Group 4,4′‐Dimethylsulfinylbenzhydryl

Zoltan Dekan, Mehdi Mobli, Michael W. Pennington, Eileen Fung, more

Angewandte Chemie > 126 > 11 > 2975 - 2978

A safety‐catch cysteine protecting group, S‐4,4′‐dimethylsulfinylbenzhydryl (Msbh), was designed and developed to expand the capabilities of synthetic strategies for the regioselective formation of disulfide bonds in cysteine‐rich peptides. The directed regioselective synthesis of human hepcidin, which contains four disulfide bonds, was undertaken and led to a high‐resolution NMR structure under more...

article

Total Synthesis of Human Hepcidin through Regioselective Disulfide‐Bond Formation by using the Safety‐Catch Cysteine Protecting Group 4,4′‐Dimethylsulfinylbenzhydryl

Zoltan Dekan, Mehdi Mobli, Michael W. Pennington, Eileen Fung, more

Angewandte Chemie International Edition > 53 > 11 > 2931 - 2934

A safety‐catch cysteine protecting group, S‐4,4′‐dimethylsulfinylbenzhydryl (Msbh), was designed and developed to expand the capabilities of synthetic strategies for the regioselective formation of disulfide bonds in cysteine‐rich peptides. The directed regioselective synthesis of human hepcidin, which contains four disulfide bonds, was undertaken and led to a high‐resolution NMR structure under more...

article

Kv1.3-Blocking Peptides from Parasitic Worms Exhibit Immunomodulatory Function

Hai M. Nguyen, Sandeep Chhabra, Shih Chieh Chang, Redwan U. Huq, more

Biophysical Journal > 2014 > 106 > 2 Supplement 1 > 739a

article

A C-terminally amidated analogue of ShK is a potent and selective blocker of the voltage-gated potassium channel Kv1.3

Michael W. Pennington, M. Harunur Rashid, Rajeev B. Tajhya, Christine Beeton, more

FEBS Letters > 2012 > 586 > 22 > 3996-4001

ShK, a 35-residue peptide from a sea anemone, is a potent blocker of potassium channels. Here we describe a new ShK analogue with an additional C-terminus Lys residue and amide. ShK-K-amide is a potent blocker of Kv1.3 and, in contrast to ShK and ShK-amide, is selective for Kv1.3. To understand this selectivity, we created complexes of ShK-K-amide with Kv1.3 and Kv1.1 using docking and molecular dynamics...

article

Expression and isotopic labelling of the potassium channel blocker ShK toxin as a thioredoxin fusion protein in bacteria

Shih Chieh Chang, Charles A. Galea, Eleanor W.W. Leung, Rajeev B. Tajhya, more

Toxicon > 2012 > 60 > 5 > 840-850

The polypeptide toxin ShK is a potent blocker of Kv1.3 potassium channels, which play a crucial role in the activation of human effector memory T-cells (T _EM ). Selective blockers constitute valuable therapeutic leads for the treatment of autoimmune diseases mediated by T _EM cells, such as multiple sclerosis, rheumatoid arthritis, and type-1 diabetes. We have established a recombinant...

article

Development of a sea anemone toxin as an immunomodulator for therapy of autoimmune diseases

Victor Chi, Michael W. Pennington, Raymond S. Norton, Eric J. Tarcha, more

Toxicon > 2012 > 59 > 4 > 529-546

Electrophysiological and pharmacological studies coupled with molecular identification have revealed a unique network of ion channels—Kv1.3, KCa3.1, CRAC (Orai1 + Stim1), TRPM7, Cl _swell —in lymphocytes that initiates and maintains the calcium signaling cascade required for activation. The expression pattern of these channels changes during lymphocyte activation and differentiation, allowing...

article

Imaging of Effector Memory T Cells during a Delayed-Type Hypersensitivity Reaction and Suppression by Kv1.3 Channel Block

Melanie P. Matheu, Christine Beeton, Adriana Garcia, Victor Chi, more

Immunity > 2008 > 29 > 4 > 602-614

Effector memory T (Tem) cells are essential mediators of autoimmune disease and delayed-type hypersensitivity (DTH), a convenient model for two-photon imaging of Tem cell participation in an inflammatory response. Shortly (3 hr) after entry into antigen-primed ear tissue, Tem cells stably attached to antigen-bearing antigen-presenting cells (APCs). After 24 hr, enlarged Tem cells were highly motile...

INFONA - science communication portal

Search results for: Michael W. Pennington

K_V1.3 channels are novel determinants of macrophage‐dependent endothelial dysfunction in angiotensin II‐induced hypertension in mice

Biophysical basis for Kv1.3 regulation of membrane potential changes induced by P2X4‐mediated calcium entry in microglia

KCa1.1 and Kv1.3 channels regulate the interactions between fibroblast-like synoviocytes and T lymphocytes during rheumatoid arthritis

Synthesis, folding, structure and activity of a predicted peptide from the sea anemone Oulactis sp. with an ShKT fold

Targeting potassium channels in rheumatoid arthritis

Identification and therapeutic modulation of a pro-inflammatory subset of disease-associated-microglia in Alzheimer’s disease

Structure, folding and stability of a minimal homologue from Anemonia sulcata of the sea anemone potassium channel blocker ShK

Enantioselective synthesis of Fmoc-l-3-(2-benzothienyl)alanine (2-BtAla) via diastereoselective alkylation of a glycine equivalent

Prolonged immunomodulation in inflammatory arthritis using the selective Kv1.3 channel blocker HsTX1[R14A] and its PEGylated analog

A systems pharmacology-based approach to identify novel Kv1.3 channel-dependent mechanisms in microglial activation

Efficient Synthesis of Protected L-Phosphonophenylalanine (Ppa) Derivatives Suitable for Solid Phase Synthesis

N‐terminally extended analogues of the K⁺ channel toxin from Stichodactyla helianthus as potent and selective blockers of the voltage‐gated potassium channel Kv1.3

Buccal mucosal delivery of a potent peptide leads to therapeutically-relevant plasma concentrations for the treatment of autoimmune diseases

Total Synthesis of Human Hepcidin through Regioselective Disulfide‐Bond Formation by using the Safety‐Catch Cysteine Protecting Group 4,4′‐Dimethylsulfinylbenzhydryl

Total Synthesis of Human Hepcidin through Regioselective Disulfide‐Bond Formation by using the Safety‐Catch Cysteine Protecting Group 4,4′‐Dimethylsulfinylbenzhydryl

Kv1.3-Blocking Peptides from Parasitic Worms Exhibit Immunomodulatory Function

A C-terminally amidated analogue of ShK is a potent and selective blocker of the voltage-gated potassium channel Kv1.3

Expression and isotopic labelling of the potassium channel blocker ShK toxin as a thioredoxin fusion protein in bacteria

Development of a sea anemone toxin as an immunomodulator for therapy of autoimmune diseases

Imaging of Effector Memory T Cells during a Delayed-Type Hypersensitivity Reaction and Suppression by Kv1.3 Channel Block

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