Annalisa Zuccotti

Publications (4)21.23 Total impact

• Article: CaV1.3-Driven SK Channel Activation Regulates Pacemaking and Spike Frequency Adaptation in Mouse Chromaffin Cells.

  David H F Vandael, Annalisa Zuccotti, Joerg Striessnig, Emilio Carbone
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  ABSTRACT: Mouse chromaffin cells (MCCs) fire spontaneous action potentials (APs) at rest. Ca(v)1.3 L-type calcium channels sustain the pacemaker current, and their loss results in depolarized resting potentials (V(rest)), spike broadening, and remarkable switches into depolarization block after BayK 8644 application. A functional coupling between Ca(v)1.3 and BK channels has been reported but cannot fully account for the aforementioned observations. Here, using Ca(v)1.3(-/-) mice, we investigated the role of Ca(v)1.3 on SK channel activation and how this functional coupling affects the firing patterns induced by sustained current injections. MCCs express SK1-3 channels whose tonic currents are responsible for the slow irregular firing observed at rest. Percentage of frequency increase induced by apamin was found inversely correlated to basal firing frequency. Upon stimulation, MCCs build-up Ca(v)1.3-dependent SK currents during the interspike intervals that lead to a notable degree of spike frequency adaptation (SFA). The major contribution of Ca(v)1.3 to the subthreshold Ca(2+) charge during an AP-train rather than a specific molecular coupling to SK channels accounts for the reduced SFA of Ca(v)1.3(-/-) MCCs. Low adaptation ratios due to reduced SK activation associated with Ca(v)1.3 deficiency prevent the efficient recovery of Na(V) channels from inactivation. This promotes a rapid decline of AP amplitudes and facilitates early onset of depolarization block following prolonged stimulation. Thus, besides serving as pacemaker, Ca(v)1.3 slows down MCC firing by activating SK channels that maintain Na(V) channel availability high enough to preserve stable AP waveforms, even upon high-frequency stimulation of chromaffin cells during stress responses.
  Journal of Neuroscience 11/2012; 32(46):16345-16359. · 7.11 Impact Factor
• Article: Equal sensitivity of Cav1.2 and Cav1.3 channels to the opposing modulations of PKA and PKG in mouse chromaffin cells.

  Satyajit Mahapatra, Andrea Marcantoni, Annalisa Zuccotti, Valentina Carabelli, Emilio Carbone
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  ABSTRACT: Key points • Cav1.2 and Cav1.3 L-type calcium channels are highly expressed in rat and mouse chromaffin cells. Beside shaping and pacemaking action potential trains, they regulate vesicle exocytosis and endocytosis. • L-type channels are opposingly regulated by the cAMP-PKA and cGMP-PKG pathways and their Ca(2+) current can undergo marked up and down changes. To date, most of the reported findings on L-type channel modulation derive from the cardiac Cav1.2 isoform. • Here, using wild-type and Cav1.3 knock out (KO) mouse chromaffin cells we show that, like Cav1.2, Cav1.3 channels are effectively modulated by PKA and PKG at basal conditions and during maximal PKA/PKG stimulation. The extent of modulation is nearly equal for both Cav1 channel isoforms. • PKA and PKG pathways act independently on Cav1.2 and Cav1.3, producing cumulative effects that are mostly visible when activating PKA and inhibiting PKG, or vice versa. Under these conditions the L-type Ca(2+) current can undergo changes of one order of magnitude. • These extreme Cav1 channel modulations are likely to occur during different physiological conditions of the adrenal gland: 'fight-or-flight' response vs. relaxed states.
  The Journal of Physiology 07/2012; 590(Pt 20):5053-73. · 4.72 Impact Factor
• Article: Ca(v)1.3 and BK channels for timing and regulating cell firing.

  David Henry Vandael, Andrea Marcantoni, Satyajit Mahapatra, Anton Caro, Peter Ruth, Annalisa Zuccotti, Marlies Knipper, Emilio Carbone
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  ABSTRACT: L-type Ca(2+) channels (LTCCs, Ca(v)1) open readily during membrane depolarization and allow Ca(2+) to enter the cell. In this way, LTCCs regulate cell excitability and trigger a variety of Ca(2+)-dependent physiological processes such as: excitation-contraction coupling in muscle cells, gene expression, synaptic plasticity, neuronal differentiation, hormone secretion, and pacemaker activity in heart, neurons, and endocrine cells. Among the two major isoforms of LTCCs expressed in excitable tissues (Ca(v)1.2 and Ca(v)1.3), Ca(v)1.3 appears suitable for supporting a pacemaker current in spontaneously firing cells. It has steep voltage dependence and low threshold of activation and inactivates slowly. Using Ca(v)1.3(-/-) KO mice and membrane current recording techniques such as the dynamic and the action potential clamp, it has been possible to resolve the time course of Ca(v)1.3 pacemaker currents that regulate the spontaneous firing of dopaminergic neurons and adrenal chromaffin cells. In several cell types, Ca(v)1.3 is selectively coupled to BK channels within membrane nanodomains and controls both the firing frequency and the action potential repolarization phase. Here we review the most critical aspects of Ca(v)1.3 channel gating and its coupling to large conductance BK channels recently discovered in spontaneously firing neurons and neuroendocrine cells with the aim of furnishing a converging view of the role that these two channel types play in the regulation of cell excitability.
  Molecular Neurobiology 11/2010; 42(3):185-98. · 5.74 Impact Factor
• Article: Modulation of Cav1.3 Ca2+ channel gating by Rab3 interacting molecule.

  Mathias Gebhart, Gabriella Juhasz-Vedres, Annalisa Zuccotti, Niels Brandt, Jutta Engel, Alexander Trockenbacher, Gurjot Kaur, Gerald J Obermair, Marlies Knipper, Alexandra Koschak, Jörg Striessnig
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  ABSTRACT: Neurotransmitter release and spontaneous action potentials during cochlear inner hair cell (IHC) development depend on the activity of Ca(v)1.3 voltage-gated L-type Ca(2+) channels. Their voltage- and Ca(2+)-dependent inactivation kinetics are slower than in other tissues but the underlying molecular mechanisms are not yet understood. We found that Rab3-interacting molecule-2alpha (RIM2alpha) mRNA is expressed in immature cochlear IHCs and the protein co-localizes with Ca(v)1.3 in the same presynaptic compartment of IHCs. Expression of RIM proteins in tsA-201 cells revealed binding to the beta-subunit of the channel complex and RIM-induced slowing of both Ca(2+)- and voltage-dependent inactivation of Ca(v)1.3 channels. By inhibiting inactivation, RIM induced a non-inactivating current component typical for IHC Ca(v)1.3 currents which should allow these channels to carry a substantial window current during prolonged depolarizations. These data suggest that RIM2 contributes to the stabilization of Ca(v)1.3 gating kinetics in immature IHCs.
  Molecular and Cellular Neuroscience 04/2010; 44(3):246-59. · 3.66 Impact Factor