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CAMP Modulation of the cytoplasmic domain in the HCN2 channel investigated by molecular simulations.

ABSTRACT: The hyperpolarization-activated cyclic nucleotide-modulated (HCN) cation channels are opened by membrane hyperpolarization, while their activation is modulated by the binding of cyclic adenosine monophosphate (cAMP) in the cytoplasm. Here we investigate the molecular basis of cAMP channel modulation by performing molecular dynamics simulations of a segment comprising the C-linker and the cyclic nucleotide binding domain (CNBD) in the presence and absence of cAMP, based on the available crystal structure of HCN2 from mouse. In presence of cAMP, the protein undergoes an oscillation of the quaternary structure on the order of 10 ns, not observed in the apoprotein. In contrast, the absence of ligand causes conformational rearrangements within the CNBDs, driving these domains to a more flexible state, similar to that described in CNBDs of other proteins. This increased flexibility causes a rather disordered movement of the CNBDs, resulting in an inhibitory effect on the channel. We propose that the cAMP-triggered large-scale oscillation plays an important role for the channel's function, being coupled to a motion of the C-linker which, in turn, modulates the gating of the channel.

SUBMITTER: Berrera M

PROVIDER: S-EPMC1440727 | biostudies-literature | 2006 May

REPOSITORIES: biostudies-literature

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cAMP Modulation of the cytoplasmic domain in the HCN2 channel investigated by molecular simulations.

Berrera Marco M Pantano Sergio S Carloni Paolo P

Biophysical journal 20060224 10

The hyperpolarization-activated cyclic nucleotide-modulated (HCN) cation channels are opened by membrane hyperpolarization, while their activation is modulated by the binding of cyclic adenosine monophosphate (cAMP) in the cytoplasm. Here we investigate the molecular basis of cAMP channel modulation by performing molecular dynamics simulations of a segment comprising the C-linker and the cyclic nucleotide binding domain (CNBD) in the presence and absence of cAMP, based on the available crystal s ...[more]

PMID: 16500960

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Project description:Sodium channels are chief proteins involved in electrical signaling in the nervous system, enabling critical functions like heartbeat and brain activity. New high-resolution X-ray structures for bacterial sodium channels have created an opportunity to see how these proteins operate at the molecular level. An important challenge to overcome is establishing relationships between the structures and functions of mammalian and bacterial channels. Bacterial sodium channels are known to exhibit the main structural features of their mammalian counterparts, as well as several key functional characteristics, including selective ion conduction, voltage-dependent gating, pore-based inactivation and modulation by local anesthetic, antiarrhythmic and antiepileptic drugs. Simulations have begun to shed light on each of these features in the past few years. Despite deviations in selectivity signatures for bacterial and mammalian channels, simulations have uncovered the nature of the multiion conduction mechanism associated with Na(+) binding to a high-field strength site established by charged glutamate side chains. Simulations demonstrated a surprising level of flexibility of the protein, showing that these side chains are active participants in the permeation process. They have also uncovered changes in protein structure, leading to asymmetrical collapses of the activation gate that have been proposed to correspond to inactivated structures. These observations offer the potential to examine the mechanisms of state-dependent drug activity, focusing on pore-blocking and pore-based slow inactivation in bacterial channels, without the complexities of inactivation on multiple timescales seen in eukaryotic channels. Simulations have provided molecular views of the interactions of drugs, consistent with sites predicted in mammalian channels, as well as a wealth of other sites as potential new drug targets. In this chapter, we survey the new insights into sodium channel function that have emerged from studies of simpler bacterial channels, which provide an excellent learning platform, and promising avenues for mechanistic discovery and pharmacological development.

Dataset Information

CAMP Modulation of the cytoplasmic domain in the HCN2 channel investigated by molecular simulations.

Publications

cAMP Modulation of the cytoplasmic domain in the HCN2 channel investigated by molecular simulations.

Similar Datasets

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