Biomedical subjects

V Arvydas Skeberdis

Publications and source records attributed to V Arvydas Skeberdis.

3 recordsLinked to original sources

PubMed2006

Protein kinase A regulates calcium permeability of NMDA receptors.

Calcium (Ca2+) influx through NMDA receptors (NMDARs) is essential for synaptogenesis, experience-dependent synaptic remodeling and plasticity. The NMDAR-mediated rise in postsynaptic Ca2+ activates a network of kinases and phosphatases that promote persistent changes in synaptic strength, such as long-term potentiation (LTP). Here we show that the Ca2+ permeability of neuronal NMDARs is under the control of the cyclic AMP-protein kinase A (cAMP-PKA) signaling cascade. PKA blockers reduced the relative fractional Ca2+ influx through NMDARs as determined by reversal potential shift analysis and by a combination of electrical recording and Ca2+ influx measurements in rat hippocampal neurons in culture and hippocampal slices from mice. In slices, PKA blockers markedly inhibited NMDAR-mediated Ca2+ rises in activated dendritic spines, with no significant effect on synaptic current. Consistent with this, PKA blockers depressed the early phase of NMDAR-dependent LTP at hippocampal Schaffer collateral-CA1 (Sch-CA1) synapses. Our data link PKA-dependent synaptic plasticity to Ca2+ signaling in spines and thus provide a new mechanism whereby PKA regulates the induction of LTP.

Animals↗

PubMed2004

Postsynaptic density protein-95 regulates NMDA channel gating and surface expression.

NMDA receptors (NMDARs) colocalize with postsynaptic density protein-95 (PSD-95), a multivalent synaptic scaffolding protein and core component of the postsynaptic density, at excitatory synapses. Although much is known about the identity and properties of scaffolding proteins, little is known about their actions on NMDAR function. Here we show that association of PSD-95 with NMDARs modulates channel gating and surface expression. PSD-95 increases the number of functional channels at the cell surface and channel opening rate of NMDARs, with little or no change in conductance, reversal potential, or mean open time. We show further that PSD-95 increases NMDAR surface expression by increasing the rate of channel insertion and decreasing the rate of channel internalization. The PDZ (PSD-95, discs large, zona occludens-1) binding motif at the distal end of the NR2 C-terminal tail is critical to the actions of PSD-95 on NMDAR function and surface expression. Given that activity bi-directionally modifies synaptic levels of PSD-95, our findings suggest a novel mechanism for activity-dependent regulation of NMDARs at central synapses.

Amino Acid Motifs↗

PubMed2003

Role of cyclic nucleotide phosphodiesterase isoforms in cAMP compartmentation following beta2-adrenergic stimulation of ICa,L in frog ventricular myocytes.

The role of cyclic nucleotide phosphodiesterase (PDE) isoforms in the beta2-adrenergic stimulation of the L-type Ca2+ current (ICa,L) was investigated in frog ventricular myocytes using double patch-clamp and double-barrelled microperfusion techniques. Isoprenaline (ISO, 1 nM to 10 microM) was applied on one half of the cell, either alone or in the presence of PDE inhibitors, and the local and distant responses of ICa,L were used to determine the gradient of local vs. distant cAMP concentration (alpha). IBMX (100 microM), a non-selective PDE inhibitor, reduced alpha from 40 to 4.4 indicating a 9-fold reduction in intracellular cAMP compartmentation when all PDE activity was blocked. While PDE1 and PDE2 inhibition had no effect, PDE3 inhibition by milrinone (3 microM) or PDE4 inhibition by Ro 20-1724 (3 microM) reduced alpha by 6- and 4-fold, respectively. A simultaneous application of milrinone and Ro 20-1724 produced a similar effect to IBMX, showing that PDE3 and PDE4 were the major PDEs accounting for cAMP compartmentation. Okadaic acid (3 microM), a non-selective phosphatase inhibitor, or H89 (1 microM), an inhibitor of cAMP-dependent protein kinase (PKA), had no effect on the distant response of ICa,L to ISO indicating that PDE activation by PKA played a minor role in cAMP compartmentation. Our results demonstrate that PDE activity determines the degree of cAMP compartmentation in frog ventricular cells upon beta2-adrenergic stimulation. PDE3 and PDE4 subtypes play a major role in this process, and contribute equally to ensure a functional coupling of beta2-adrenergic receptors with nearby Ca2+ channels via local elevations of cAMP.

3',5'-Cyclic-AMP Phosphodiesterases↗