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Viral channel forming proteins - modeling the target.

ABSTRACT: The cellular and subcellular membranes encounter an important playground for the activity of membrane proteins encoded by viruses. Viral membrane proteins, similar to their host companions, can be integral or attached to the membrane. They are involved in directing the cellular and viral reproduction, the fusion and budding processes. This review focuses especially on those integral viral membrane proteins which form channels or pores, the classification to be so, modeling by in silico methods and potential drug candidates. The sequence of an isolate of Vpu from HIV-1 is aligned with host ion channels and a toxin. The focus is on the alignment of the transmembrane domains. The results of the alignment are mapped onto the 3D structures of the respective channels and toxin. The results of the mapping support the idea of a 'channel-pore dualism' for Vpu.

SUBMITTER: Fischer WB

PROVIDER: S-EPMC7094444 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature

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Viral channel forming proteins - modeling the target.

Fischer Wolfgang B WB Hsu Hao-Jen HJ

Biochimica et biophysica acta 20100528 2

The cellular and subcellular membranes encounter an important playground for the activity of membrane proteins encoded by viruses. Viral membrane proteins, similar to their host companions, can be integral or attached to the membrane. They are involved in directing the cellular and viral reproduction, the fusion and budding processes. This review focuses especially on those integral viral membrane proteins which form channels or pores, the classification to be so, modeling by in silico methods a ...[more]

PMID: 20546700

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Project description:Pregnenolone is a neurosteroid that modulates glial growth and differentiation, neuronal firing, and several brain functions, these effects being attributed to pregnenolone actions on the neurons and glial cells themselves. Despite the vital role of the cerebral circulation for brain function and the fact that pregnenolone is a vasoactive agent, pregnenolone action on brain arteries remain unknown. Here, we obtained in vivo concentration response curves to pregnenolone on middle cerebral artery (MCA) diameter in anesthetized male and female C57BL/6J mice. In both male and female animals, pregnenolone (1 nM-100 μM) constricted MCA in a concentration-dependent manner, its maximal effect reaching ~22-35% decrease in diameter. Pregnenolone action was replicated in intact and de-endothelialized, in vitro pressurized MCA segments with pregnenolone evoking similar constriction in intact and de-endothelialized MCA. Neurosteroid action was abolished by 1 μM paxilline, a selective blocker of Ca2+ - and voltage-gated K+ channels of large conductance (BK). Cell-attached, patch-clamp recordings on freshly isolated smooth muscle cells from mouse MCAs demonstrated that pregnenolone at concentrations that constricted MCAs in vitro and in vivo (10 μM), reduced BK activity (NPo), with an average decrease in NPo reaching 24.2%. The concentration-dependence of pregnenolone constriction of brain arteries and inhibition of BK activity in intact cells were paralleled by data obtained in cell-free, inside-out patches, with maximal inhibition reached at 10 μM pregnenolone. MCA smooth muscle BKs include channel-forming α (slo1 proteins) and regulatory β1 subunits, encoded by KCNMA1 and KCNMB1, respectively. However, pregnenolone-driven decrease in NPo was still evident in MCA myocytes from KCNMB1-/- mice. Following reconstitution of slo1 channels into artificial, binary phospholipid bilayers, 10 μM pregnenolone evoked slo1 NPo inhibition which was similar to that seen in native membranes. Lastly, pregnenolone failed to constrict MCA from KCNMA1-/- mice. In conclusion, pregnenolone constricts MCA independently of neuronal, glial, endothelial and circulating factors, as well as of cell integrity, organelles, complex membrane cytoarchitecture, and the continuous presence of cytosolic signals. Rather, this action involves direct inhibition of SM BK channels, which does not require β1 subunits but is mediated through direct sensing of the neurosteroid by the channel-forming α subunit.

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Viral channel forming proteins - modeling the target.

Publications

Viral channel forming proteins - modeling the target.

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