Linked Life Data

12582169

Source:http://linkedlifedata.com/resource/pubmed/id/12582169

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
16
pubmed:dateCreated
2003-4-14
pubmed:abstractText
I(f), encoded by the hyperpolarization-activated cyclic nucleotide-modulated (HCN) channel family, is a key player in cardiac and neuronal pacing. Although HCN channels structurally resemble voltage-gated K(+) (Kv) channels, their structure-function correlation is much less clear. Here we probed the functional importance of the HCN1 S3-S4 linker by multiple substitutions of its residues. Neutralizing Glu(235), an acidic S3-S4 linker residue conserved in all hyperpolarization-activated channels, by Ala substitution produced a depolarizing activation shift (V(12) = -65.0 +/- 0.7 versus -70.6 +/- 0.7 mV for wild-type HCN1); the charge-reversed mutation E235R shifted activation even more positively (-56.2 +/- 0.5 mV). Increasing external Mg(2+) mimicked the progressive rightward shifts of E235A and E235R by gradually shifting activation (V(12) = 1 < 3 < 10 < 30 mm); Delta V(12) induced by 30 mm Mg(2+) was significantly attenuated for E235A (+7.9 +/- 1.2 versus +11.3 +/- 0.9 mV for wild-type HCN1) and E235R (+3.3 +/- 1.4 mV) channels, as if surface charges were already shielded. Consistent with an electrostatic role, the energetic changes associated with Delta V(12) resulting from various Glu(235) substitutions (i.e. Asp, Ala, Pro, His, Lys, and Arg) displayed a strong correlation with their charges (Delta Delta G = -2.1 +/- 0.3 kcal/mol/charge; r = 0.94). In contrast, D233E, D233A, D233G, and D233R did not alter activation gating. D233C (in C318S background) was also not externally accessible when probed with methanethiosulfonate ethylammonium (MTSEA). We conclude that the S3-S4 linker residue Glu(235) influences activation gating, probably by acting as a surface charge.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Apr
pubmed:issn
0021-9258
pubmed:author
pubmed:issnType
Print
pubmed:day
18
pubmed:volume
278
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
13647-54
pubmed:dateRevised
2007-11-15
pubmed:meshHeading
pubmed-meshheading:12582169-Alanine, pubmed-meshheading:12582169-Amino Acid Motifs, pubmed-meshheading:12582169-Amino Acid Sequence, pubmed-meshheading:12582169-Animals, pubmed-meshheading:12582169-Cyclic Nucleotide-Gated Cation Channels, pubmed-meshheading:12582169-Electrophysiology, pubmed-meshheading:12582169-Glutamic Acid, pubmed-meshheading:12582169-Ion Channels, pubmed-meshheading:12582169-Kinetics, pubmed-meshheading:12582169-Magnesium, pubmed-meshheading:12582169-Membrane Potentials, pubmed-meshheading:12582169-Mice, pubmed-meshheading:12582169-Molecular Sequence Data, pubmed-meshheading:12582169-Mutation, pubmed-meshheading:12582169-Nerve Tissue Proteins, pubmed-meshheading:12582169-Oocytes, pubmed-meshheading:12582169-Potassium, pubmed-meshheading:12582169-Potassium Channels, pubmed-meshheading:12582169-Protein Structure, Tertiary, pubmed-meshheading:12582169-Sequence Homology, Amino Acid, pubmed-meshheading:12582169-Thermodynamics, pubmed-meshheading:12582169-Xenopus
pubmed:year
2003
pubmed:articleTitle
Identification of a surface charged residue in the S3-S4 linker of the pacemaker (HCN) channel that influences activation gating.
pubmed:affiliation
Institute of Molecular Cardiobiology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S., Research Support, Non-U.S. Gov't