New calcium channel agonists as potential therapeutics in Lambert–Eaton myasthenic syndrome and other neuromuscular diseases

Tarr, Tyler B.; Valdomir, Guillermo; Liang, Mary; Wipf, Peter; Meriney, Stephen D.

doi:10.1111/nyas.12001

Cited by 13 publications

(13 citation statements)

References 63 publications

(79 reference statements)

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“…Our results from P/Q-type channels expressed in HEK cells confirmed the prolongation of calcium tail currents, supporting the published effects on channel deactivation (Cho and Meriney, 2006). The augmentation of synaptic transmission, along with the motility rescue, both further the idea that administration of roscovitine or its chemical derivatives (Tarr et al, 2012) to patients with LEMS may have benefits beyond the actions on the associated lung tumor. The identification of the zebrafish P/Q mutant line now offers an ideal platform for electrophysiological assessment of the effectiveness of pharmacological derivatives in treatment of congenital LEMs.…”

Section: Discussionmentioning

confidence: 91%

“…The results from expressed P/Q- and N-type channels (Buraei et al, 2007) and frog NMJ (Cho and Meriney, 2006) both support the direct agonist action involving slowed channel deactivation. The evidence for phosphorylation independent regulation comes from a roscovitine analogue that has weak CDK inhibitor activity, but strongly promotes calcium entry (Tarr et al, 2012). Thus, roscovitine may represent an agonist for P/Q- and N-type channels, similar to BAY K analogues that act on L-type channels.…”

Section: Discussionmentioning

confidence: 99%

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Zebrafish Calls for Reinterpretation for the Roles of P/Q Calcium Channels in Neuromuscular Transmission

et al. 2013

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A long-held tenet of neuromuscular transmission is that calcium-dependent neurotransmitter release is mediated by N-type calcium channels in frog but P/Q-type channels in mammals. The N-type assignment in frog is based principally on pharmacological sensitivity to ω-conotoxin GVIA. Our studies show that zebrafish neuromuscular transmission is also sensitive to ω-conotoxin GVIA. However, positional cloning of a mutant line with compromised neuromuscular function identified a mutation in a P/Q- rather than N-type channel. Cloning and heterologous expression of this P/Q-type channel confirmed a block by ω-conotoxin GVIA raising the likelihood that all vertebrates, including frog, utilize the P/Q-type calcium channel for neuromuscular transmission. Additionally, our P/Q defective mutant line offered a means of testing the ability of roscovitine, known to potentiate frog neuromuscular transmission, to mediate behavioral and functional rescue. Acute treatment led to rapid improvement of both, pointing to potential therapeutic benefit for myasthenic disorders involving calcium channel dysfunction.

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Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Zebrafish Calls for Reinterpretation for the Roles of P/Q Calcium Channels in Neuromuscular Transmission

et al. 2013

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“…R-roscovitine slows calcium channel deactivation, prolongs the mean open time and thereby increases total calcium entry. This results in increased neurotransmitter release, which might be useful in the symptomatic treatment of LEMS [59,60]. However, the inhibition of Cdks by R-roscovitine results in an arrest in cell cycle progression and induction of cell death, which are potential sources of undesirable side effects.…”

Section: Future Developmentsmentioning

confidence: 97%

“…Future research will indicate whether calcium channel agonists will have a role in the symptomatic treatment of LEMS, either as monotherapy or in combination with 3,4-DAP. Researchers hypothesized a synergetic effect of the combination of both substances [60,61].…”

Section: Future Developmentsmentioning

confidence: 99%

Treatment options for Lambert–Eaton myasthenic syndrome

Sonderen

Wirtz

Verschuuren

et al. 2014

Expert Opinion on Orphan Drugs

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Introduction: Lambert--Eaton myasthenic syndrome (LEMS) is a rare autoimmune disorder of the neuromuscular junction. Antibody-mediated functional loss of voltage-gated calcium channels (VGCCs) on the presynaptic surface results in reduced neurotransmitter release. Muscle weakness starts in the proximal limbs and is accompanied by autonomic failure and areflexia. About 50 --60% of the patients have small-cell lung cancer (SCLC), with antibodies produced in reaction to VGCC on tumor cells. In non-tumor LEMS, an autoimmune reaction causes antibody production. Knowledge of the pathophysiology of antibody production in SCLC-LEMS and non-tumor LEMS and a detailed understanding of the neuromuscular junction and its dysfunction in LEMS is needed for drug development. Areas covered: This review gives an overview of the clinical symptoms, diagnosis and pathophysiology of LEMS. Current treatment options and results of recent research on newly developed symptomatic treatment are described. Expert opinion: Extensive search for SCLC is needed in LEMS patients. Appropriate tumor treatment should be started in SCLC-LEMS. In both SCLC-LEMS and non-tumor LEMS, symptomatic treatment consists of 3,4-diaminopyridine. If insufficient, pyridostigmine can be added, although a small trial failed to prove its benefit in LEMS and it is probably only efficient in a subset of patients. In moderate-to-severe disease, immunosuppressive treatment with prednisolone and azathioprine should be started. Research on drugs in LEMS is complicated by the infrequency of the disorder. Future developments are mainly expected in the field of symptomatic treatment. Possibly, further studies on immunosuppression in myasthenia gravis will be meaningful for the therapeutic strategy in LEMS as well.

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“…Moreover, only a few synthetic compounds have been developed that activate Ca V channels, and most of these selectively agonize Ca V 1 subtypes [68,69]. Thus, the ability of the centipede venom toxin ω- (hereafter Ssm1a) to activate Ca V channel currents in rat dorsal root ganglion neurons (which contain predominantly Ca V 2 and Ca V 3 subtypes) is unique for a venom peptide [28].…”

Section: ω-Slptx-ssm1a: a Unique Ca V Channel Agonistmentioning

confidence: 99%

Centipede venoms as a source of drug leads

Undheim

Jenner

King

2016

Expert Opinion on Drug Discovery

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Introduction: Centipedes are one of the oldest and most successful lineages of venomous terrestrial predators. Despite their use for centuries in traditional medicine, centipede venoms remain poorly studied. However, recent work indicates that centipede venoms are highly complex chemical arsenals that are rich in disulfide-constrained peptides that have novel pharmacology and three-dimensional structure. Areas covered:This review summarizes what is currently know about centipede venom proteins, with a focus on disulfide-rich peptides that have novel or unexpected pharmacology that might be useful from a therapeutic perspective. We also highlight the remarkable diversity of constrained threedimensional peptide scaffolds present in these venoms that might be useful for bioengineering of drug leads. Expert opinion:The resurgence of interest in peptide drugs has stimulated interest in venoms as a source of highly stable, disulfide-constrained peptides with potential as therapeutics. Well-studied venomous taxa such as cone snails and snakes have yielded FDA-approved drugs, while ancient invertebrate predators such as spiders and sea anemones have yielded molecules that are currently in preclinical studies and clinical trials, respectively. However, until recently, the paucity of research on centipede venoms made it easy to discount them as a potential source of peptides with therapeutically useful properties. Seminal studies over the past five years have revealed that centipede venoms have exceedingly complex proteomes that are perhaps richer than any other venom in unique disulfide-rich peptide scaffolds. Like most arthropod predators, centipede venoms are rich in peptides that target neuronal ion channels and receptors, but it is also becoming increasingly apparent that many of these peptides have novel or unexpected pharmacological properties with potential applications in drug discovery and development.

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New calcium channel agonists as potential therapeutics in Lambert–Eaton myasthenic syndrome and other neuromuscular diseases

Cited by 13 publications

References 63 publications

Zebrafish Calls for Reinterpretation for the Roles of P/Q Calcium Channels in Neuromuscular Transmission

Zebrafish Calls for Reinterpretation for the Roles of P/Q Calcium Channels in Neuromuscular Transmission

Treatment options for Lambert–Eaton myasthenic syndrome

Centipede venoms as a source of drug leads

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