Dataset Information

Impaired Fear Extinction Due to a Deficit in Ca2+ Influx Through L-Type Voltage-Gated Ca2+ Channels in Mice Deficient for Tenascin-C.

ABSTRACT: Mice deficient in the extracellular matrix glycoprotein tenascin-C (TNC-/-) express a deficit in specific forms of hippocampal synaptic plasticity, which involve the L-type voltage-gated Ca2+ channels (L-VGCCs). The mechanisms underlying this deficit and its functional implications for learning and memory have not been investigated. In line with previous findings, we report on impairment in theta-burst stimulation (TBS)-induced long-term potentiation (LTP) in TNC-/- mice in the CA1 hippocampal region and its rescue by the L-VGCC activator Bay K-8644. We further found that the overall pattern of L-VGCC expression in the hippocampus in TNC-/- mice was normal, but Western blot analysis results uncovered upregulated expression of the Cav1.2 and Cav1.3 α-subunits of L-VGCCs. However, these L-VGCCs were not fully functional in TNC-/- mice, as demonstrated by Ca2+ imaging, which revealed a reduction of nifedipine-sensitive Ca2+ transients in CA1 pyramidal neurons. TNC-/- mice showed normal learning and memory in the contextual fear conditioning paradigm but impaired extinction of conditioned fear responses. Systemic injection of the L-VGCC blockers nifedipine and diltiazem into wild-type mice mimicked the impairment of fear extinction observed in TNC-/- mice. The deficiency in TNC-/- mice substantially occluded the effects of these drugs. Our results suggest that TNC-mediated modulation of L-VGCC activity is essential for fear extinction.

SUBMITTER: Morellini F

PROVIDER: S-EPMC5539374 | biostudies-other | 2017

REPOSITORIES: biostudies-other

ACCESS DATA

Similar Datasets

Project description:Voltage-dependent Na+ channel activation underlies action potential generation fundamental to cellular excitability. In skeletal and cardiac muscle this triggers contraction via ryanodine-receptor (RyR)-mediated sarcoplasmic reticular (SR) Ca2+ release. We here review potential feedback actions of intracellular [Ca2+] ([Ca2+]i) on Na+ channel activity, surveying their structural, genetic and cellular and functional implications, translating these to their possible clinical importance. In addition to phosphorylation sites, both Nav1.4 and Nav1.5 possess potentially regulatory binding sites for Ca2+ and/or the Ca2+-sensor calmodulin in their inactivating III-IV linker and C-terminal domains (CTD), where mutations are associated with a range of skeletal and cardiac muscle diseases. We summarize in vitro cell-attached patch clamp studies reporting correspondingly diverse, direct and indirect, Ca2+ effects upon maximal Nav1.4 and Nav1.5 currents (Imax) and their half-maximal voltages (V1/2) characterizing channel gating, in cellular expression systems and isolated myocytes. Interventions increasing cytoplasmic [Ca2+]i down-regulated Imax leaving V1/2 constant in native loose patch clamped, wild-type murine skeletal and cardiac myocytes. They correspondingly reduced action potential upstroke rates and conduction velocities, causing pro-arrhythmic effects in intact perfused hearts. Genetically modified murine RyR2-P2328S hearts modelling catecholaminergic polymorphic ventricular tachycardia (CPVT), recapitulated clinical ventricular and atrial pro-arrhythmic phenotypes following catecholaminergic challenge. These accompanied reductions in action potential conduction velocities. The latter were reversed by flecainide at RyR-blocking concentrations specifically in RyR2-P2328S as opposed to wild-type hearts, suggesting a basis for its recent therapeutic application in CPVT. We finally explore the relevance of these mechanisms in further genetic paradigms for commoner metabolic and structural cardiac disease.

Project description:Circulating hormones stimulate the phospholipase C? (PLC)/Ca(2+) influx pathway to regulate numerous cell functions, including vascular tone. It was proposed previously that Ca(2+)-independent phospholipase A(2) (iPLA(2))-dependent store-operated Ca(2+) influx channels mediate hormone-induced contractions in isolated arteries, because bromoenol lactone (BEL), a potent irreversible inhibitor of iPLA(2), inhibited such contractions. However, the effects of BEL on other channels implicated in mediating hormone-induced vessel contractions, specifically voltage-gated Ca(2+) (Ca(V)1.2) and transient receptor potential canonical (TRPC) channels, have not been defined clearly. Using isometric tension measurements, we found that thapsigargin-induced contractions were ?34% of those evoked by phenylephrine or KCl. BEL completely inhibited not only thapsigargin- but also phenylephrine- and KCl-induced ring contractions, suggesting that Ca(V)1.2 and receptor-operated TRPC channels also may be sensitive to BEL. Therefore, we investigated the effects of BEL on heterologously expressed Ca(V)1.2 and TRPC channels in human embryonic kidney cells, a model system that allows probing of individual protein function without interference from other signaling elements of native cells. We found that low micromolar concentrations of BEL inhibited Ca(V)1.2, TRPC5, TRPC6, and heteromeric TRPC1-TRPC5 channels in an iPLA(2)-independent manner. BEL also attenuated PLC activity, suggesting that the compound may inhibit TRPC channel activity in part by interfering with an initial PLC-dependent step required for TRPC channel activation. Conversely, BEL did not affect endogenous voltage-gated K(+) channels in human embryonic kidney cells. Our findings support the hypothesis that iPLA(2)-dependent store-operated Ca(2+) influx channels and iPLA(2)-independent hormone-operated TRPC channels can serve as smooth muscle depolarization triggers to activate Ca(V)1.2 channels and to regulate vascular tone.

Dataset Information

Impaired Fear Extinction Due to a Deficit in Ca2+ Influx Through L-Type Voltage-Gated Ca2+ Channels in Mice Deficient for Tenascin-C.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure