Expression and 1,4-Dihydropyridine-Binding Properties of Brain L-Type Calcium Channel Isoforms

Sinnegger-Brauns, Martina J.; Huber, Irene; Koschak, Alexandra; Wild, Claudia; Obermair, Gerald J.; Einzinger, Ursula; Hoda, Jean-Charles; Sartori, Simone; Striessnig, Jörg

doi:10.1124/mol.108.049981

Cited by 189 publications

(167 citation statements)

References 28 publications

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“…Neuroprotective effects of isradipine are achieved at the plasma concentration that is obtained within the safe dose range for human administration10, 11 and consistent with the tolerable dosage identified in our phase II study of isradipine in PD (STEADY‐PDII) 12. Isradipine is the most potent of the clinically available Cav1.3 DHPs and has excellent central nervous system penetration suggesting it is the optimal DHP to target this novel mechanism of neuroprotection 13, 14…”

Section: Introductionsupporting

confidence: 71%

A novel design of a Phase III trial of isradipine in early Parkinson disease (STEADY‐PD III)

Biglan

Oakes

Lang

et al. 2017

Ann Clin Transl Neurol

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ObjectiveTo describe the rationale for a novel study design and baseline characteristics of a disease‐modifying trial of isradipine 10 mg daily in early Parkinson disease (PD).Methods STEADY‐PDIII is a 36‐month, Phase 3, parallel group, placebo‐controlled study of the efficacy of isradipine 10 mg daily in 336 participants with early PD as measured by the change in the Unified Parkinson Disease Rating Scale (UPDRS) Part I‐III score in the practically defined ON state. Secondary outcome measures include clinically meaningful measures of disability progression in early PD: (1) Time to initiation and utilization of dopaminergic therapy; (2) Time to onset of motor complications; (3) Change in nonmotor disability. Exploratory measures include global measures of functional disability, quality of life, change in the ambulatory capacity, cognitive function, and pharmacokinetic analysis. Rationale for the current design and alternative design approaches are discussed.ResultsThe entire cohort of 336 participants was enrolled at 55 Parkinson Study Group sites in North America. The percentage of male participants were 68.5% with a mean age of 61.9 years (sd 9.0), mean Hoehn and Yahr stage of 1.7 (sd 0.5), mean UPDRS total of 23.1 (sd 8.6), and MoCA of 28.1 (sd 1.4).Interpretation STEADY‐PD III has a novel and innovative design allowing for the determination of longer duration benefits on clinically relevant outcomes in a relatively small cohort on top of the benefit derived from symptomatic therapy. Baseline characteristics are similar to those in previously enrolled de novo PD trials. This study represents a unique opportunity to evaluate the potential impact of a novel therapy to slow progression of PD disability and provide clinically meaningful benefits.

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Section: Introductionsupporting

confidence: 71%

A novel design of a Phase III trial of isradipine in early Parkinson disease (STEADY‐PD III)

Biglan

Oakes

Lang

et al. 2017

Ann Clin Transl Neurol

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“…Employing quantitative TaqMan RT-PCR analysis, we determined whether and how much mRNA of the four ␤ subunits is expressed in hippocampus tissue of 2-week-old BALB/c mice and in cultured hippocampal neurons (40,41). 4 In hippocampus, we detected similar expression levels of all ␤ subunit isoforms.…”

Section: Cultured Hippocampal Neurons Express Mrna and Protein Of Allmentioning

confidence: 99%

“…Quantitative TaqMan RT-PCR-The relative abundance of different ␤ transcripts was assessed by quantitative RT-PCR using a standard curve method as described elsewhere (40,41). 4 The following specific TaqMan gene expression assays, designed to span exon-exon boundaries, were purchased from Applied Biosystems (Foster City, CA): ␤ 1 , Mm00518940_m1; ␤ 2 , Mm00659092_m1; ␤ 3 , Mm00432233_m1; and ␤ 4 , Mm00521623_m1.…”

Section: Rna Isolation and Reverse Transcription-2-week-oldmentioning

confidence: 99%

Reciprocal Interactions Regulate Targeting of Calcium Channel β Subunits and Membrane Expression of α1 Subunits in Cultured Hippocampal Neurons

Obermair

Schlick

Biase

et al. 2010

Journal of Biological Chemistry

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Auxiliary ␤ subunits modulate current properties and mediate the functional membrane expression of voltage-gated Ca 2؉ channels in heterologous cells. In brain, all four ␤ isoforms are widely expressed, yet little is known about their specific roles in neuronal functions. Here, we investigated the expression and targeting properties of ␤ subunits and their role in membrane expression of Ca V 1.2 ␣ 1 subunits in cultured hippocampal neurons. Quantitative reverse transcription-PCR showed equal expression, and immunofluorescence showed a similar distribution of all endogenous ␤ subunits throughout dendrites and axons. High resolution microscopy of hippocampal neurons transfected with six different V5 epitope-tagged ␤ subunits demonstrated that all ␤ subunits were able to accumulate in synaptic terminals and to colocalize with postsynaptic Ca V 1.2, thus indicating a great promiscuity in ␣ 1 -␤ interactions. In contrast, restricted axonal targeting of ␤ 1 and weak colocalization of ␤ 4b with Ca V 1.2 indicated isoform-specific differences in local channel complex formation. Membrane expression of external hemagglutinin epitope-tagged Ca V 1.2 was strongly enhanced by all ␤ subunits in an isoform-specific manner. Conversely, mutating the ␣-interaction domain of Ca V 1.2 (W440A) abolished membrane expression and targeting into dendritic spines. This demonstrates that in neurons the interaction of a ␤ subunit with the ␣-interaction domain is absolutely essential for membrane expression of ␣ 1 subunits, as well as for the subcellular localization of ␤ subunits, which by themselves possess little or no targeting properties.Voltage-gated Ca 2ϩ channels (Ca V ) 3 provide key pathways for Ca 2ϩ entry into neurons and translate membrane depolarization into neurotransmitter secretion and gene regulation.Ca V s are composed of a pore-forming ␣ 1 subunit and the auxiliary ␣ 2 ␦ and ␤ subunits (1). Whereas the ␣ 1 subunits are responsible for voltage sensing and ion conduction, the auxiliary subunits have been implicated in membrane targeting and modulation of channel properties (for review see Ref.2). Presynaptic Ca V s regulate neurotransmitter release (3), and postsynaptic Ca V s activate the transcriptional regulators cAMP-response element-binding protein (CREB) and nuclear factor of activated T-cells (NFAT) (4, 5) and thus modulate long term potentiation (6). These functions reflect both the diversity of Ca V isoforms expressed in brain (7-11) and their differential subcellular localization in neurons (12-15).Four distinct ␤ isoforms have been identified (16 -19), all of which are expressed in brain (20 -23). They contain an Src homology 3 domain and a guanylate kinase domain (24 -27). However, the guanylate kinase fold is modified so that it can bind with high affinity to the so-called ␣-interaction domain (AID) in the intracellular I-II linker of Ca V ␣ 1 subunits (28, 29). The Src homology 3 and the guanylate kinase-like domains are highly conserved among the four genes encoding ␤ subunits (Cacnb1-b4; Fig. 1C), whereas t...

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“…The L-type calcium channels used by SNc DA neurons in pacemaking have a distinctive Cav1.3 pore-forming subunit encoded by Cacna1d (21, 111). Cav1.3 calcium channels are relatively rare, constituting only about 10% of the all the L-type calcium channels found in the brain (107). Channels with this subunit differ from other L-type calcium channels in that they open at relatively hyperpolarized potentials, allowing them to contribute to the mechanisms driving the membrane potential to spike threshold underlying autonomous pacemaking (21,43,96).…”

Section: Cell-specific Factors In Pdmentioning

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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Expression and 1,4-Dihydropyridine-Binding Properties of Brain L-Type Calcium Channel Isoforms

Abstract: The

Cited by 189 publications

References 28 publications

A novel design of a Phase III trial of isradipine in early Parkinson disease (STEADY‐PD III)

A novel design of a Phase III trial of isradipine in early Parkinson disease (STEADY‐PD III)

Reciprocal Interactions Regulate Targeting of Calcium Channel β Subunits and Membrane Expression of α1 Subunits in Cultured Hippocampal Neurons

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

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