Dataset Information

Distinct perinatal features of the hyperpolarization-activated non-selective cation current I(h) in the rat cortical plate.

ABSTRACT:

Background

During neocortical development, multiple voltage- and ligand-gated ion channels are differentially expressed in neurons thereby shaping their intrinsic electrical properties. One of these voltage-gated ion channels, the hyperpolarization-activated cyclic nucleotide-gated (HCN) channel and its current I(h), is an important regulator of neuronal excitability. Thus far, studies on an early I(h) appearance in rodent neocortex are missing or conflicting. Therefore, we focused our study on perinatal neocortical I(h) and its properties.

Results

In the perinatal rat neocortex we observed a rapid increase in the number of neurons exhibiting I(h). Perinatal I(h) had unique properties: first, a pronounced cAMP sensitivity resulting in a marked shift of the voltage sufficient for half-maximum activation of the current towards depolarized voltages and second, an up to 10 times slower deactivation at physiological membrane potentials when compared to the one at postnatal day 30. The combination of these features was sufficient to suppress membrane resonance in our in silico and in vitro experiments. Although all four HCN subunits were present on the mRNA level we only detected HCN4, HCN3 and HCN1 on the protein level at P0. HCN1 protein at P0, however, appeared incompletely processed. At P30 glycosilated HCN1 and HCN2 dominated. By in silico simulations and heterologous co-expression experiments of a 'slow' and a 'fast' I(h) conducting HCN channel subunit in HEK293 cells, we mimicked most characteristics of the native current, pointing to a functional combination of subunit homo- or heteromeres.

Conclusion

Taken together, these data indicate a HCN subunit shift initiated in the first 24 hours after birth and implicate a prominent perinatal role of the phylogenetically older HCN3 and/or HCN4 subunits in the developing neocortex.

SUBMITTER: Battefeld A

PROVIDER: S-EPMC3518177 | biostudies-literature | 2012 Jun

REPOSITORIES: biostudies-literature

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Publications

Distinct perinatal features of the hyperpolarization-activated non-selective cation current I(h) in the rat cortical plate.

Battefeld Arne A Rocha Nino N Stadler Konstantin K Bräuer Anja U AU Strauss Ulf U

Neural development 20120613

<h4>Background</h4>During neocortical development, multiple voltage- and ligand-gated ion channels are differentially expressed in neurons thereby shaping their intrinsic electrical properties. One of these voltage-gated ion channels, the hyperpolarization-activated cyclic nucleotide-gated (HCN) channel and its current I(h), is an important regulator of neuronal excitability. Thus far, studies on an early I(h) appearance in rodent neocortex are missing or conflicting. Therefore, we focused our s ...[more]

PMID: 22694806

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Project description:Lipopolysaccharide (LPS) has been implicated in sepsis-mediated heart failure and chronic cardiac myopathies. We determined that LPS directly and reversibly affects cardiac myocyte function by altering regulation of intracellular Ca2+ concentration ([Ca2+]i) in immortalized cardiomyocytes, HL-1 cells. [Ca2+]i oscillated (<0.4 Hz), displaying slow and transient components. LPS (1 microg/ml), derived either from Escherichia coli or from Salmonella enteritidis, reversibly abolished Ca2+ oscillations and decreased basal [Ca2+]i by 30-40 nM. HL-1 cells expressed Toll-like receptors, i.e., TLR-2 and TLR-4. Thus, we differentiated effects of LPS on [Ca2+]i and Ca2+ oscillations by addition of utlrapure LPS, a TLR-4 ligand. Ultrapure LPS had no effect on basal [Ca2+]i, but it reduced the rate of Ca2+ oscillations. Interestingly, Pam3CSK4, a TLR-2 ligand, affected neither Ca2+ parameter, and the effect of ultrapure LPS and Pam3CSK4 combined was similar to that of utlrapure LPS alone. Thus, unpurified LPS directly inhibits HL-1 calcium metabolism via TLR-4 and non-TLR-4-dependent mechanisms. Since others have shown that endotoxin impairs the hyperpolarization-activated, nonselective cationic pacemaker current (I(f)), which is expressed in HL-1 cells, we utilized whole cell voltage-clamp techniques to demonstrate that LPS (1 microg/ml) reduced I(f) in HL-1 cells. This inhibition was marginal at physiologic membrane potentials and significant at very negative potentials (P < 0.05 at -140, -150, and -160 mV). So, we also evaluated effects of LPS on tail currents of fully activated I(f). LPS reduced the slope conductance of the tail currents from 498 +/- 140 pS/pF to 223 +/- 65 pS/pF (P < 0.05) without affecting reversal potential of -11 mV. Ultrapure LPS had similar effect on I(f), whereas Pam3CSK4 had no effect on I(f). We conclude that LPS inhibits activation of I(f), enhances its deactivation, and impairs regulation of [Ca2+]i in HL-1 cardiomyocytes via TLR-4 and other mechanisms.

Dataset Information

Distinct perinatal features of the hyperpolarization-activated non-selective cation current I(h) in the rat cortical plate.

Background

Results

Conclusion

Publications

Distinct perinatal features of the hyperpolarization-activated non-selective cation current I(h) in the rat cortical plate.

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