Article
Pharmacology & Pharmacy
Ruth D. D. Lee, Yi-Je Chen, Latika Singh, Hai M. M. Nguyen, Heike Wulff
Summary: Mechanical thrombectomy has improved outcomes for acute ischemic stroke, but there is a need for immunocytoprotective therapies to reduce inflammation and prevent reperfusion injury. K(V)1.3 inhibitors have shown potential in improving outcomes, and this study compared a peptidic and a small molecule blocker. The small molecule PAP-1 provided benefits even when started 72 hours after reperfusion, while the peptide ShK-223 did not reduce infarction or neurological deficits. PAP-1 does not affect the activity of tissue plasminogen activator.
FRONTIERS IN PHARMACOLOGY
(2023)
Article
Biochemical Research Methods
Dorothy C. C. Wai, Muhammad Umair Naseem, Gabor Mocsar, Sanjeevini Babu Reddiar, Yijun Pan, Agota Csoti, Peter Hajdu, Cameron Nowell, Joseph A. Nicolazzo, Gyorgy Panyi, Raymond S. Norton
Summary: Upregulation of the voltage-gated potassium channel K(V)1.3 is associated with autoimmune and neuroinflammatory diseases. A peptide analogue called HsTX1[R14A] has high affinity for K(V)1.3 and can be visualized using fluorescence imaging. This research is significant for understanding the biology of K(V)1.3 and developing treatments for related diseases.
BIOCONJUGATE CHEMISTRY
(2022)
Article
Pharmacology & Pharmacy
Agota Csoti, Rosby del Carmen Najera Meza, Ferenc Bogar, Gabor Tajti, Tibor G. Szanto, Zoltan Varga, Georgina B. Gurrola, Gabor K. Toth, Lourival D. Possani, Gyorgy Panyi
Summary: Kv1.3 K+ channels are important in regulating T cell activation and Ca2+ signaling. The novel peptide toxin sVmKTx derived from V. mexicanus smithi shows increased selectivity for Kv1.3 and potential therapeutic application in autoimmune diseases.
BIOCHEMICAL PHARMACOLOGY
(2022)
Article
Chemistry, Medicinal
Spela Gubic, Alberto Montalbano, Cesare Sala, Andrea Becchetti, Louise Antonia Hendrickx, Kenny M. Van Theemsche, Ernesto Lopes Pinheiro-Junior, Ginevra Chioccioli Altadonna, Steve Peigneur, Janez Ilas, Alain J. Labro, Luis A. Pardo, Jan Tytgat, Tihomir Tomasic, Annarosa Arcangeli, Lucija Peterlin Masic
Summary: In this study, the structure-activity relationship, KV1.3 inhibition, and immunosuppressive effects of new thiophene-based KV1.3 inhibitors were investigated. The new KV1.3 inhibitor trans-18 showed nanomolar potency in inhibiting KV1.3-mediated current in T-lymphocytes, Ltk- cells, and Xenopus laevis oocytes. Furthermore, these inhibitors impaired intracellular Ca2+ signaling and suppressed T-cell activation, proliferation, and colony formation.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Biology
Jesusa Capera, Mireia Perez-Verdaguer, Roberta Peruzzo, Maria Navarro-Perez, Juan Martinez-Pinna, Armando Alberola-Die, Andres Morales, Luigi Leanza, Ildiko Szabo, Antonio Felipe
Summary: The voltage-gated potassium channel Kv1.3 plays a dual role in immune cells and cancer cells, with its different cellular locations leading to involvement in distinct physiological processes.
Article
Plant Sciences
Cheng-Gao Zhou, Zhi-Nan Xiang, Ning Zhao, Xing Sun, Zhuo-Fan Hu, Jia-Le Wu, Ru-Feng Xia, Chen Chen, Jun-Cheng Su, Jia-Chun Chen, Luo-Sheng Wan
Summary: In this study, a total of 17 new jatrophane diterpenoids, named heliojatrone D (1) and helioscopids A-P (2-17), were isolated and identified from the whole plant of Euphorbia helioscopia. Additionally, 11 known analogues (18-28) were also found. The inhibitory effect of these compounds against Kv1.3 ion channels was evaluated, and two compounds (2 and 15) showed the most potent activity with IC50 values of 0.9 μM.
JOURNAL OF NATURAL PRODUCTS
(2022)
Article
Multidisciplinary Sciences
Purushotham Selvakumar, Ana I. Fernandez-Marino, Nandish Khanra, Changhao He, Alice J. Paquette, Bing Wang, Ruiqi Huang, Vaughn V. Smider, William J. Rice, Kenton J. Swartz, Joel R. Meyerson
Summary: This study reports the structures of the Kv1.3 potassium channel and its role in immune modulation. By examining the interaction of nanobody and antibody-toxin fusion with the Kv1.3 channel, two distinct mechanisms to inhibit Kv1.3 channel activity were identified.
NATURE COMMUNICATIONS
(2022)
Review
Biochemistry & Molecular Biology
Alla F. Fomina, Hai M. Nguyen, Heike Wulff
Summary: In the past 5 years, inhibitors of the potassium channel K(V)1.3 have been shown to reduce neuroinflammation in various disease models by reducing microglia activation and suppressing pro-inflammatory cytokines and nitric oxide production. Recent studies have revealed that K(V)1.3 channels not only regulate membrane potential, but also play a crucial role in regulating calcium influx in microglia, similar to their role in T cells.
Article
Pharmacology & Pharmacy
Jong-Hui Kim, Soobeen Hwang, Su-Hyun Jo
Summary: PCB19, as a NDL-PCB, can acutely block the Kv1.3 channel in a concentration-dependent manner with a irreversible effect on the channels activation and inactivation properties, while showing selective inhibition on Kv1.3 over Kv1.5 channel at the same concentrations.
TOXICOLOGY AND APPLIED PHARMACOLOGY
(2021)
Review
Pharmacology & Pharmacy
Seow Theng Ong, Anu Tyagi, K. George Chandy, Shashi Bhushan
Summary: This study utilizes cryogenic electron microscopy and molecular dynamics simulation to reveal the specific mechanism of C-type inactivation. The study finds that C-type inactivation is initiated by the rupture of an intra-subunit hydrogen bond, leading to the separation of the selectivity filter from the pore helix. Additionally, the study also discovers that the peptide dalazatide can partially reverse this process.
FRONTIERS IN PHARMACOLOGY
(2022)
Article
Multidisciplinary Sciences
Yuqing Wang, Duolong Zhu, Laura C. Ortiz-Velez, Jacob L. Perry, Michael W. Pennington, Joseph M. Hyser, Robert A. Britton, Christine Beeton
Summary: Engineered probiotic delivery system was developed to deliver a peptide to the intestinal tract effectively, showing great potential for the treatment of chronic inflammatory disorders and metabolic disease.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Article
Multidisciplinary Sciences
Supriya Ramesha, Sruti Rayaprolu, Christine A. Bowen, Cynthia R. Giver, Sara Bitarafan, Hai M. Nguyen, Tianwen Gao, Michael J. Chen, Ngozi Nwabueze, Eric B. Dammer, Amanda K. Engstrom, Hailian Xiao, Andrea Pennati, Nicholas T. Seyfried, David J. Katz, Jacques Galipeau, Heike Wulff, Edmund K. Waller, Levi B. Wood, Allan Levey, Srikant Rangaraju
Summary: By studying Kv1.3-expressing CNS-MPs in AD mouse models, researchers have identified unique molecular features of these cells and confirmed their microglial origin. Blocking Kv1.3 channels in vivo resulted in reduced Aβ burden, increased anti-inflammatory CNS-MPs, and a prophagocytic phenotype in AD mouse models.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Article
Multidisciplinary Sciences
Yuqing Wang, Duolong Zhu, Laura C. Ortiz-Velez, Jacob L. Perry, Michael W. Pennington, Joseph M. Hyser, Robert A. Britton, Christine Beeton
Summary: Engineered probiotic Lactobacillus reuteri was developed to deliver the Kv1.3 potassium blocker ShK-235 (LrS235) to the intestinal tract with high efficacy. The LrS235 culture supernatants showed the ability to block Kv1.3 currents and inhibit human T effector memory (TEM) lymphocyte proliferation in vitro. Oral administration of LrS235 effectively reduced inflammation in a delayed-type hypersensitivity model of atopic dermatitis and clinical signs of disease and joint inflammation in a model of rheumatoid arthritis.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Article
Cell Biology
Krishnan K. Mahadevan, Valerie S. Lebleu, Elena Ramirez, Yang Chen, Bingrui Li, Amari M. Sockwell, Mihai Gagea, Hikaru Sugimoto, Lakshmi Kavitha Sthanam, Desiree Tampe, Michael Zeisberg, Haoqiang Ying, Abhinav K. Jain, Ronald A. Depinho, Anirban Maitra, Kathleen M. Mcandrews, Raghu Kalluri
Summary: Oncogenic KRASG12D is critical for PDAC and represses tumor immunity. Elimination of KRAS* leads to reactivation of FAS and CD8+ T cell-mediated apoptosis, promoting tumor eradication. High KRAS expression in PDAC tumors is associated with lower proportion of CD8+ T cells and shorter survival. Combination of KRAS* targeting with immunotherapy can control PDAC effectively.
DEVELOPMENTAL CELL
(2023)
Article
Multidisciplinary Sciences
Albert Vallejo-Gracia, Daniel Sastre, Magali Colomer-Molera, Laura Sole, Maria Navarro-Perez, Jesusa Capera, Sara R. Roig, Oriol Pedros-Gamez, Irene Estadella, Orsolya Szilagyi, Gyorgy Panyi, Peter Hajdu, Antonio Felipe
Summary: KCNE4 serves as a crucial regulator in modulating immune system physiology by controlling Kv1.3-associated leukocyte functions.
SCIENTIFIC REPORTS
(2021)
Article
Immunology
Itsuro Kazama, Yoshio Maruyama, Yoshimichi Murata
IMMUNOPHARMACOLOGY AND IMMUNOTOXICOLOGY
(2012)
Article
Physiology
Atsushi Ohsaga, Yoshimichi Murata, Yoshiaki Kondo, Riichiro Hira, Yoshio Maruyama
JOURNAL OF PHYSIOLOGICAL SCIENCES
(2008)
Review
Neurosciences
Yasushi Okamura, Yoshimichi Murata, Hirohide Iwasaki
JOURNAL OF PHYSIOLOGY-LONDON
(2009)
Article
Multidisciplinary Sciences
Hirohide Iwasaki, Yoshimichi Murata, Youngjun Kim, Md. Israil Hossain, Carolyn A. Worby, Jack E. Dixon, Thomas McCormack, Takehiko Sasaki, Yasushi Okamura
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2008)
Article
Neurosciences
Yoshimichi Murata, Yasushi Okamura
JOURNAL OF PHYSIOLOGY-LONDON
(2007)
Article
Cell Biology
Y Okamura, A Nishino, Y Murata, K Nakajo, H Iwasaki, Y Ohtsuka, M Tanaka-Kunishima, N Takahashi, Y Hara, T Yoshida, M Nishida, H Okado, H Watari, IA Meinertzhagen, N Satoh, K Takahashi, Y Satou, Y Okada, Y Mori
PHYSIOLOGICAL GENOMICS
(2005)
Article
Multidisciplinary Sciences
Y Murata, H Iwasaki, M Sasaki, K Inaba, Y Okamura
Article
Neurosciences
Y Murata, Y Fujiwara, Y Kubo
JOURNAL OF PHYSIOLOGY-LONDON
(2002)
Article
Multidisciplinary Sciences
O Saitoh, Y Murata, M Odagiri, M Itoh, H Itoh, T Misaka, Y Kubo
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2002)
Article
Biochemistry & Molecular Biology
Y Murata, H Okado, Y Kubo
JOURNAL OF BIOLOGICAL CHEMISTRY
(2001)
Article
Neurosciences
Y Kubo, Y Murata
JOURNAL OF PHYSIOLOGY-LONDON
(2001)
Article
Urology & Nephrology
Itsuro Kazama, Yasuhiro Endo, Hiroaki Toyama, Yutaka Ejima, Shin Kurosawa, Yoshimichi Murata, Mitsunobu Matsubara, Yoshio Maruyama