Receptor Sites for Open Channel Blockers of Shaker Voltage-Gated Potassium Channels – Molecular Approaches

1993 ◽  
Vol 13 (1-4) ◽  
pp. 503-512 ◽  
Author(s):  
Olaf Pongs
Keyword(s):  
Potassium Channels ◽  
Open Channel ◽  
Channel Blockers ◽  
Voltage Gated ◽  
Molecular Approaches ◽  
Receptor Sites

scholarly journals Structure-activity relationship studies of three novel 4-aminopyridine K+ channel blockers

2019 ◽  
Author(s):  
Sofia Rodríguez-Rangel ◽  
Alyssa D. Bravin ◽  
Karla M. Ramos-Torres ◽  
Pedro Brugarolas ◽  
Jorge E. Sánchez-Rodríguez
Keyword(s):  
Multiple Sclerosis ◽  
Potassium Channels ◽  
Symptomatic Treatment ◽  
K Channel ◽  
Channel Blockers ◽  
Rodent Models ◽  
Voltage Gated ◽  
Structure Activity ◽  
Pet Tracer ◽  
Ph Conditions

Abstract4-Aminopyridine (4AP) is a specific blocker of voltage-gated potassium channels (KV1 family) clinically approved for the symptomatic treatment of patients with multiple sclerosis (MS). It has recently been shown that [18F]3F4AP, a radiofluorinated analog of 4AP, also binds to KV1 channels and can be used as a PET tracer for the detection of demyelinated lesions in rodent models of MS. Here, we investigate three novel 4AP derivatives containing methyl (-CH3), methoxy (-OCH3) and trifluoromethyl (-CF3) in the 3 position as potential candidates for PET imaging and/or therapy. We characterized the physicochemical properties of these compounds (pKa and logD) and analyzed their ability to block Shaker K+ channel under different voltage and pH conditions. Our results demonstrate that all three derivatives are able to block voltage-gated potassium channels. Specifically, 3-methyl-4-aminopyridine (3Me4AP) was found to be approximately 7-fold more potent than 4AP, whereas the methoxy (3MeO4AP) and trifluoromethyl (3CF34AP) containing compounds were about 3- to 4-fold less potent than 4AP, respectively. These results suggest that these novel derivatives are potential candidates for therapy and imaging.

scholarly journals Molecular Proximity of Kv1.3 Voltage-gated Potassium Channels and β1-Integrins on the Plasma Membrane of Melanoma Cells

2002 ◽  
Vol 120 (1) ◽  
pp. 29-37 ◽  
Author(s):  
Vira V. Artym ◽  
Howard R. Petty
Keyword(s):  
Potassium Channels ◽  
Tumor Cell ◽  
Cell Membranes ◽  
Resonance Energy Transfer ◽  
Resonance Energy ◽  
K Channel ◽  
Channel Blockers ◽  
Voltage Gated ◽  
Β1 Integrins ◽  
Kv1.3 Channels

Tumor cell membranes have multiple components that participate in the process of metastasis. The present study investigates the physical association of β1-integrins and Kv1.3 voltage-gated potassium channels in melanoma cell membranes using resonance energy transfer (RET) techniques. RET between donor-labeled anti–β1-integrin and acceptor-labeled anti-Kv1.3 channels was detected on LOX cells adherent to glass and fibronectin-coated coverslips. However, RET was not observed on LOX cells in suspension, indicating that molecular proximity of these membrane molecules is adherence-related. Several K+ channel blockers, including tetraethylammonium, 4-aminopyridine, and verapamil, inhibited RET between β1-integrins and Kv1.3 channels. However, the irrelevant K+ channel blocker apamin had no effect on RET between β1-integrins and Kv1.3 channels. Based on these findings, we speculate that the lateral association of Kv1.3 channels with β1-integrins contributes to the regulation of integrin function and that channel blockers might affect tumor cell behavior by influencing the assembly of supramolecular structures containing integrins.

Blockers of voltage-gated K channels inhibit proliferation of cultured brown fat cells

1993 ◽  
Vol 264 (4) ◽  
pp. C1014-C1019 ◽  
Author(s):  
P. A. Pappone ◽  
S. I. Ortiz-Miranda
Keyword(s):  
Cell Proliferation ◽  
Potassium Channels ◽  
Potassium Channel ◽  
Culture Conditions ◽  
Brown Fat ◽  
Neonatal Rat ◽  
Channel Blockers ◽  
Continuous Exposure ◽  
Fat Cells ◽  
Voltage Gated

Cultured brown fat cells have both voltage- and Ca(2+)-activated potassium channels. We tested whether potassium channel activity is necessary for brown fat proliferation by growing adipocytes and preadipocytes from neonatal rat brown fat in the presence of potassium channel blockers. Whole cell patch-clamp experiments showed that verapamil, nifedipine, and quinine block the voltage-gated potassium current (IK,V) with micromolar affinity. Ca(2+)-activated currents (IK,NE) could be activated by micromolar intracellular Ca2+ concentrations and were blocked by nanomolar concentrations of apamin. Both IK,V and IK,NE are blocked by millimolar concentrations of tetraethylammonium (TEA). Under standard culture conditions, the number of cells showing the multilocular morphology characteristic of brown fat cells doubled in 3-5 days. Continuous exposure to 100 nM norepinephrine had no effect on this process. Cell proliferation was inhibited by TEA, quinine, or verapamil. The inhibition was dose dependent, with concentrations for half-block of cell proliferation similar to the Kd values for block of IK,V. Apamin, which selectively blocks IK,NE, had no effect on cell growth. These results suggest that functional voltage-gated potassium channels, but not Ca(2+)-activated potassium channels, may be necessary for the normal proliferation of brown fat cells in culture.

scholarly journals Structure-activity relationship studies of four novel 4-aminopyridine K+ channel blockers

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Sofia Rodríguez-Rangel ◽  
Alyssa D. Bravin ◽  
Karla M. Ramos-Torres ◽  
Pedro Brugarolas ◽  
Jorge E. Sánchez-Rodríguez
Keyword(s):  
Multiple Sclerosis ◽  
Potassium Channels ◽  
Symptomatic Treatment ◽  
K Channel ◽  
Channel Blockers ◽  
Rodent Models ◽  
Voltage Gated ◽  
Structure Activity ◽  
Pet Tracer ◽  
Ph Conditions

Abstract4-Aminopyridine (4AP) is a specific blocker of voltage-gated potassium channels (KV1 family) clinically approved for the symptomatic treatment of patients with multiple sclerosis (MS). It has recently been shown that [18F]3F4AP, a radiofluorinated analog of 4AP, also binds to KV1 channels and can be used as a PET tracer for the detection of demyelinated lesions in rodent models of MS. Here, we investigate four novel 4AP derivatives containing methyl (-CH3), methoxy (-OCH3) as well as trifluoromethyl (-CF3) in the 2 and 3 position as potential candidates for PET imaging and/or therapy. We characterized the physicochemical properties of these compounds (basicity and lipophilicity) and analyzed their ability to block Shaker K+ channel under different voltage and pH conditions. Our results demonstrate that three of the four derivatives are able to block voltage-gated potassium channels. Specifically, 3-methyl-4-aminopyridine (3Me4AP) was found to be approximately 7-fold more potent than 4AP and 3F4AP; 3-methoxy- and 3-trifluoromethyl-4-aminopyridine (3MeO4AP and 3CF34AP) were found to be about 3- to 4-fold less potent than 4AP; and 2-trifluoromethyl-4-AP (2CF34AP) was found to be about 60-fold less active. These results suggest that these novel derivatives are potential candidates for therapy and imaging.

scholarly journals A Cation–π Interaction between Extracellular TEA and an Aromatic Residue in Potassium Channels

2006 ◽  
Vol 128 (6) ◽  
pp. 649-657 ◽  
Author(s):  
Christopher A. Ahern ◽  
Amy L. Eastwood ◽  
Henry A. Lester ◽  
Dennis A. Dougherty ◽  
Richard Horn
Keyword(s):  
Open Channel ◽  
Nonsense Suppression ◽  
Channel Blockers ◽  
Binding Ability ◽  
Aromatic Residue ◽  
Voltage Gated ◽  
High Affinity ◽  
Suppression Method ◽  
High Level

Open-channel blockers such as tetraethylammonium (TEA) have a long history as probes of the permeation pathway of ion channels. High affinity blockade by extracellular TEA requires the presence of an aromatic amino acid at a position that sits at the external entrance of the permeation pathway (residue 449 in the eukaryotic voltage-gated potassium channel Shaker). We investigated whether a cation–π interaction between TEA and such an aromatic residue contributes to TEA block using the in vivo nonsense suppression method to incorporate a series of increasingly fluorinated Phe side chains at position 449. Fluorination, which is known to decrease the cation–π binding ability of an aromatic ring, progressively increased the inhibitory constant Ki for the TEA block of Shaker. A larger increase in Ki was observed when the benzene ring of Phe449 was substituted by nonaromatic cyclohexane. These results support a strong cation–π component to the TEA block. The data provide an empirical basis for choosing between Shaker models that are based on two classes of reported crystal structures for the bacterial channel KcsA, showing residue Tyr82 in orientations either compatible or incompatible with a cation–π mechanism. We propose that the aromatic residue at this position in Shaker is favorably oriented for a cation–π interaction with the permeation pathway. This choice is supported by high level ab initio calculations of the predicted effects of Phe modifications on TEA binding energy.

scholarly journals Presynaptic Paraneoplastic Disorders of the Neuromuscular Junction: An Update

2021 ◽  
Vol 11 (8) ◽  
pp. 1035
Author(s):  
Maria Pia Giannoccaro ◽  
Patrizia Avoni ◽  
Rocco Liguori
Keyword(s):  
Potassium Channels ◽  
Neuromuscular Junction ◽  
Calcium Channels ◽  
Myasthenia Gravis ◽  
Neuromuscular Transmission ◽  
Voltage Gated ◽  
Voltage Gated Calcium Channels ◽  
Immune Mediated ◽  
Recent Developments ◽  
Myasthenic Syndrome

The neuromuscular junction (NMJ) is the target of a variety of immune-mediated disorders, usually classified as presynaptic and postsynaptic, according to the site of the antigenic target and consequently of the neuromuscular transmission alteration. Although less common than the classical autoimmune postsynaptic myasthenia gravis, presynaptic disorders are important to recognize due to the frequent association with cancer. Lambert Eaton myasthenic syndrome is due to a presynaptic failure to release acetylcholine, caused by antibodies to the presynaptic voltage-gated calcium channels. Acquired neuromyotonia is a condition characterized by nerve hyperexcitability often due to the presence of antibodies against proteins associated with voltage-gated potassium channels. This review will focus on the recent developments in the autoimmune presynaptic disorders of the NMJ.

scholarly journals Voltage-gated calcium channel blockers for psychiatric disorders: genomic reappraisal

2019 ◽  
Vol 216 (5) ◽  
pp. 250-253 ◽  
Author(s):  
Paul J. Harrison ◽  
Elizabeth M. Tunbridge ◽  
Annette C. Dolphin ◽  
Jeremy Hall
Keyword(s):  
Calcium Channels ◽  
Calcium Channel ◽  
Psychiatric Disorders ◽  
Calcium Channel Blockers ◽  
Channel Blockers ◽  
Risk Genes ◽  
Voltage Gated ◽  
Voltage Gated Calcium Channels ◽  
Voltage Gated Calcium Channel ◽  
Second Use

SummaryWe reappraise the psychiatric potential of calcium channel blockers (CCBs). First, voltage-gated calcium channels are risk genes for several disorders. Second, use of CCBs is associated with altered psychiatric risks and outcomes. Third, research shows there is an opportunity for brain-selective CCBs, which are better suited to psychiatric indications.

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