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The molecular architecture of dihydropyrindine receptor/L-type Ca2+ channel complex.

ABSTRACT: Dihydropyridine receptor (DHPR), an L-type Ca(2+) channel complex, plays an essential role in muscle contraction, secretion, integration of synaptic input in neurons and synaptic transmission. The molecular architecture of DHPR complex remains elusive. Here we present a 15-Å resolution cryo-electron microscopy structure of the skeletal DHPR/L-type Ca(2+) channel complex. The DHPR has an asymmetrical main body joined by a hook-like extension. The main body is composed of a "trapezoid" and a "tetrahedroid". Homologous crystal structure docking and site-specific antibody labelling revealed that the ?1 and ?2 subunits are located in the "trapezoid" and the ? subunit is located in the "tetrahedroid". This structure revealed the molecular architecture of a eukaryotic Ca(2+) channel complex. Furthermore, this structure provides structural insights into the key elements of DHPR involved in physical coupling with the RyR/Ca(2+) release channel and shed light onto the mechanism of excitation-contraction coupling.

SUBMITTER: Hu H

PROVIDER: S-EPMC4322351 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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The molecular architecture of dihydropyrindine receptor/L-type Ca2+ channel complex.

Hu Hongli H Wang Zhao Z Wei Risheng R Fan Guizhen G Wang Qiongling Q Zhang Kaiming K Yin Chang-Cheng CC

Scientific reports 20150210

Dihydropyridine receptor (DHPR), an L-type Ca(2+) channel complex, plays an essential role in muscle contraction, secretion, integration of synaptic input in neurons and synaptic transmission. The molecular architecture of DHPR complex remains elusive. Here we present a 15-Å resolution cryo-electron microscopy structure of the skeletal DHPR/L-type Ca(2+) channel complex. The DHPR has an asymmetrical main body joined by a hook-like extension. The main body is composed of a "trapezoid" and a "tetr ...[more]

PMID: 25667046

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Project description:Study objectivesVoltage-gated Ca(2+) channels (VGCCs) are key elements in mediating thalamocortical rhythmicity. Low-voltage activated (LVA) CaV 3 T-type Ca(2+) channels have been related to thalamic rebound burst firing and to generation of non-rapid eye movement (NREM) sleep. High-voltage activated (HVA) CaV 1 L-type Ca(2+) channels, on the opposite, favor the tonic mode of action associated with higher levels of vigilance. However, the role of the HVA Non-L-type CaV2.3 Ca(2+) channels, which are predominantly expressed in the reticular thalamic nucleus (RTN), still remains unclear. Recently, CaV2.3(-/-) mice were reported to exhibit altered spike-wave discharge (SWD)/absence seizure susceptibility supported by the observation that CaV2.3 mediated Ca(2+) influx into RTN neurons can trigger small-conductance Ca(2+)-activated K(+)-channel type 2 (SK2) currents capable of maintaining thalamic burst activity. Based on these studies we investigated the role of CaV2.3 R-type Ca(2+) channels in rodent sleep.MethodsThe role of CaV2.3 Ca(2+) channels was analyzed in CaV2.3(-/-) mice and controls in both spontaneous and artificial urethane-induced sleep, using implantable video-EEG radiotelemetry. Data were analyzed for alterations in sleep architecture using sleep staging software and time-frequency analysis.ResultsCaV2.3 deficient mice exhibited reduced wake duration and increased slow-wave sleep (SWS). Whereas mean sleep stage durations remained unchanged, the total number of SWS epochs was increased in CaV2.3(-/-) mice. Additional changes were observed for sleep stage transitions and EEG amplitudes. Furthermore, urethane-induced SWS mimicked spontaneous sleep results obtained from CaV2.3 deficient mice. Quantitative Real-time PCR did not reveal changes in thalamic CaV3 T-type Ca(2+) channel expression. The detailed mechanisms of SWS increase in CaV2.3(-/-) mice remain to be determined.ConclusionsLow-voltage activated CaV2.3 R-type Ca(2+) channels in the thalamocortical loop and extra-thalamocortical circuitries substantially regulate rodent sleep architecture thus representing a novel potential target for pharmacological treatment of sleep disorders in the future.

Dataset Information

The molecular architecture of dihydropyrindine receptor/L-type Ca2+ channel complex.

Publications

The molecular architecture of dihydropyrindine receptor/L-type Ca2+ channel complex.

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