L‐type calcium channel blockers and Parkinson disease in Denmark

Ritz, Beate; Rhodes, Shannon; Qian, Lei; Schernhammer, Eva; Olsen, Jørgen H.; Friis, Søren

doi:10.1002/ana.21937

Cited by 246 publications

(208 citation statements)

References 23 publications

(29 reference statements)

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“…Ruthenium red has recently been shown to improve mitochondrial ATP levels and membrane potentials in neurons expressing mutant ␣-synuclein and/or PINK-1 associated with Parkinson disease (22). Furthermore, L-type calcium blockers have been suggested to reduce the chance of developing Parkinson disease (23). More recently, the selective TRPV4 channel blocker, HC-067047, has been shown to improve bladder function in experimentally induced cystitis in rodents without any major side side effects (24).…”

Section: Discussionmentioning

confidence: 99%

Mutant TRPV4-mediated Toxicity Is Linked to Increased Constitutive Function in Axonal Neuropathies

Fecto

Shi

Huda

et al. 2011

Journal of Biological Chemistry

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Mutations in TRPV4 have been linked to three distinct axonal neuropathies. However, the pathogenic mechanism underlying these disorders remains unclear. Both gain and loss of calcium channel activity of the mutant TRPV4 have been suggested. Here, we show that the three previously reported TRPV4 mutant channels have a physiological localization and display an increased calcium channel activity, leading to increased cytotoxicity in three different cell types. Patch clamp experiments showed that cells expressing mutant TRPV4 have much larger whole-cell currents than those expressing the wild-type TRPV4 channel. Single channel recordings showed that the mutant channels have higher open probability, due to a modification of gating, and no change in single-channel conductance. These data support the hypothesis that a "gain of function" mechanism, possibly leading to increased intracellular calcium influx, underlies the pathogenesis of the TRPV4-linked axonal neuropathies, and may have immediate implications for designing rational therapies.Scapuloperoneal spinal muscle atrophy (SPSMA), congenital distal spinal muscle atrophy (CDSMA), and Charcot-MarieTooth disease type 2C (CMT2C, also known as hereditary motor and sensory neuropathy type 2, HMSN IIC) are phenotypically heterogeneous and dominantly inherited disorders involving topographically distinct muscles and nerves (1, 2). Genetic linkage analysis mapped the disease loci to an overlapping region at 12q24 (3-5). Recently, it has been shown that these three axonal neuropathies are allelic disorders caused by mutations in the gene encoding the transient receptor potential cation channel, subfamily V (vanilloid), member 4 (TRPV4) 3 (6 -8). To date, seven mutations in TRPV4 have been identified in 15 families with axonal neuropathies (6 -10). Functional studies, however, yielded divergent hypotheses about the pathogenic mechanism of the diseases (6 -8, 10).In our original study, we tested two mutations, R316C and R269H, which were identified in the original SPSMA and CMT2C families, respectively (6). We found that in HEK293 cells, mutant TRPV4 had a physiological localization on the plasma membrane similar to wild-type TRPV4 (wtTRPV4). Calcium imaging showed that mutant TRPV4 had significantly increased calcium channel activity, at both basal and activated levels when compared with wtTRPV4. These findings were consistent with electrophysiological recordings, which showed a higher TRPV4 conductance in HEK293 cells expressing the R269H mutant compared with wtTRPV4. In another study, Landouré et al. (8) showed similar results in HEK293 cells and Xenopus laevis oocytes with R269H and R269C mutations. Furthermore, mutant TRPV4-mediated cytotoxicity was observed in transfected HEK293 cells and dorsal root ganglion neurons. This cytotoxicity was related to increased intracellular calcium concentrations (8). More recently, we have also shown that two other TRPV4 mutants (R232C and R316H) localize appropriately and cause reversible and toxic hypercalcemia in HEK293 and HeLa c...

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Section: Discussionmentioning

confidence: 99%

Mutant TRPV4-mediated Toxicity Is Linked to Increased Constitutive Function in Axonal Neuropathies

Fecto

Shi

Huda

et al. 2011

Journal of Biological Chemistry

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“…A case-control study of hypertensive patients found a significant reduction in the observed risk of PD with CCA use, but not with medications that reduce blood pressure in other ways (9). More recently, a large Danish data set has been examined (100 …”

Section: Surmeier Et Almentioning

confidence: 99%

The Origins of Oxidant Stress in Parkinson's Disease and Therapeutic Strategies

Surmeier

Guzmán

Sánchez-Padilla

et al. 2011

Antioxidants & Redox Signaling

135

109

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Parkinson's disease (PD) is a major world-wide health problem afflicting millions of the aged population. Factors that act on most or all cell types (pan-cellular factors), particularly genetic mutations and environmental toxins, have dominated public discussions of disease etiology. Although there is compelling evidence supporting an association between disease risk and these factors, the pattern of neuronal pathology and cell loss is difficult to explain without cell-specific factors. This article focuses on recent studies showing that the neurons at greatest risk in PD-substantia nigra pars compacta dopamine neurons-have a distinctive physiological phenotype that could contribute to their vulnerability. The opening of L-type calcium channels during autonomous pacemaking results in sustained calcium entry into the cytoplasm of substantia nigra pars compacta dopamine neurons, resulting in elevated mitochondrial oxidant stress and susceptibility to toxins used to create animal models of PD. This cellspecific stress could increase the negative consequences of pan-cellular factors that broadly challenge either mitochondrial or proteostatic competence. The availability of well-tolerated, orally deliverable antagonists for L-type calcium channels points to a novel neuroprotective strategy that could complement current attempts to boost mitochondrial function in the early stages of the disease.

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“…They have been developed as cardiovascular drugs, blocking L-type (Ca V 1) calcium channels. Amlodipine blocks Ca V 1.2 with IC 50 =100 nM and Ca V 2.1 with IC 50 =10 M. Many drugs from the group of dihydropyridines crossing blood-brain barrier, including nifedipine and nimodipine (and excluding amlodipine), proved efficacy in preventing Parkinson's disease in over 25% of patients [128]. However, in an animal study, nifedipine lowered anticonvulsant activity of topiramate in mice (it doubled its ED 50 ).…”

Section: Nifedipinementioning

confidence: 99%

Ion Channels as Drug Targets in Central Nervous System Disorders

Waszkielewicz¹,

Gunia²,

Szkaradek³

et al. 2013

CMC

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Ion channel targeted drugs have always been related with either the central nervous system (CNS), the peripheral nervous system, or the cardiovascular system. Within the CNS, basic indications of drugs are: sleep disorders, anxiety, epilepsy, pain, etc. However, traditional channel blockers have multiple adverse events, mainly due to low specificity of mechanism of action. Lately, novel ion channel subtypes have been discovered, which gives premises to drug discovery process led towards specific channel subtypes. An example is Na + channels, whose subtypes 1.3 and 1.7-1.9 are responsible for pain, and 1.1 and 1.2 -for epilepsy. Moreover, new drug candidates have been recognized. This review is focusing on ion channels subtypes, which play a significant role in current drug discovery and development process. The knowledge on channel subtypes has developed rapidly, giving new nomenclatures of ion channels. For example, Ca 2+ channels are not any more divided to T, L, N, P/Q, and R, but they are described as Ca v 1.1-Ca v 3.3, with even newer nomenclature 1A-1I and 1S. Moreover, new channels such as P2X1-P2X7, as well as TRPA1-TRPV1 have been discovered, giving premises for new types of analgesic drugs.

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L‐type calcium channel blockers and Parkinson disease in Denmark

Cited by 246 publications

References 23 publications

Mutant TRPV4-mediated Toxicity Is Linked to Increased Constitutive Function in Axonal Neuropathies

Mutant TRPV4-mediated Toxicity Is Linked to Increased Constitutive Function in Axonal Neuropathies

The Origins of Oxidant Stress in Parkinson's Disease and Therapeutic Strategies

Ion Channels as Drug Targets in Central Nervous System Disorders

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