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What can naturally occurring mutations tell us about Ca(v)1.x channel function?

ABSTRACT: Voltage-gated Ca²? channels allow for Ca²?-dependent intracellular signaling by directly mediating Ca²? ion influx, by physical coupling to intracellular Ca²? release channels or functional coupling to other ion channels such as Ca²? activated potassium channels. L-type Ca²? channels that comprise the family of Ca(v)1 channels are expressed in many electrically excitable tissues and are characterized by their unique sensitivity to dihydropyridines. In this issue, we summarize genetic defects in L-type Ca²? channels and analyze their role in human diseases (Ca²? channelopathies); e.g. mutations in Ca(v)1.2 ?1 cause Timothy and Brugada syndrome, mutations in Ca(v)1.3 ?1 are linked to sinoatrial node dysfunction and deafness while mutations in Ca(v)1.4 ?1 are associated with X-linked retinal disorders such as an incomplete form of congenital stationary night blindness. Herein, we also put the mutations underlying the channel's dysfunction into the structural context of the pore-forming ?1 subunit. This analysis highlights the importance of combining functional data with structural analysis to gain a deeper understanding for the disease pathophysiology as well as for physiological channel function. This article is part of a Special Issue entitled: Calcium channels.

SUBMITTER: Stockner T

PROVIDER: S-EPMC3787742 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

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What can naturally occurring mutations tell us about Ca(v)1.x channel function?

Stockner Thomas T Koschak Alexandra A

Biochimica et biophysica acta 20121204 7

Voltage-gated Ca²⁺ channels allow for Ca²⁺-dependent intracellular signaling by directly mediating Ca²⁺ ion influx, by physical coupling to intracellular Ca²⁺ release channels or functional coupling to other ion channels such as Ca²⁺ activated potassium channels. L-type Ca²⁺ channels that comprise the family of Ca(v)1 channels are expressed in many electrically excitable tissues and are characterized by their unique sensitivity to dihydropyridines. In this issue, we summarize genetic defects in ...[more]

PMID: 23219801

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Project description:Sequencing of Ebola virus (EBOV) genomes during the 2014-2016 epidemic identified several naturally occurring, dominant mutations potentially impacting virulence or tropism. In this study, we characterized EBOV variants carrying one of the following substitutions: A82V in the glycoprotein (GP), R111C in the nucleoprotein (NP), or D759G in the RNA-dependent RNA polymerase (L). Compared with the wild-type (WT) EBOV C07 isolate, NP and L mutants conferred a replication advantage in monkey Vero E6, human A549, and insectivorous bat Tb1.Lu cells, while L mutants displayed a disadvantage in human Huh7 cells. The replication of the GP mutant was significantly delayed in Tb1.Lu cells and similar to that of the WT in other cells. The L mutant was less virulent, as evidenced by increased survival for mice and a significantly delayed time to death for ferrets, but increased lengths of the period of EBOV shedding may have contributed to the prolonged epidemic. Our results show that single substitutions can have observable impacts on EBOV pathogenicity and provide a framework for the study of other mutations.IMPORTANCE During the Ebola virus (EBOV) disease outbreak in West Africa in 2014-2016, it was discovered that several mutations in the virus emerged and became prevalent in the human population. This suggests that these mutations may play a role impacting viral fitness. We investigated three of these previously identified mutations (in the glycoprotein [GP], nucleoprotein [NP], or RNA-dependent RNA polymerase [L]) in cell culture, as well as in mice and ferrets, by generating recombinant viruses (based on an early West African EBOV strain) each carrying one of these mutations. The NP and L mutations appear to decrease virulence, whereas the GP mutation slightly increases virulence but mainly impacts viral tropism. Our results show that these single mutations can impact EBOV virulence in animals and have implications for the rational design of efficacious antiviral therapies against these infections.

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What can naturally occurring mutations tell us about Ca(v)1.x channel function?

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What can naturally occurring mutations tell us about Ca(v)1.x channel function?

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