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The fusion pore was previously defined as a molecular structure that forms a direct contact between the vesicle lumen and the plasma membrane ( Breckenridge and Almers 1987) and modifications of the fusion pore lifetime established the participation of various proteins in exocytosis ( Wang et al. To investigate VGCC involvement in exocytosis we studied the kinetics of amperometric spikes and the mean open time of the fusion pore in single vesicles of chromaffin cells during exocytosis ( Wightman et al. More explicitly, the Ca 2+ channel acts as a Ca 2+ sensor protein during membrane depolarization, signalling secretion upstream to Ca 2+ binding to synaptotagmin. According to this model, initiation of exocytosis during membrane depolarization results from divalent cations occupying the pore of the Ca 2+ channel rather than binding to intracellular protein(s). 2002), the VGCC has been proposed as an alternative candidate for the Ca 2+ sensor protein in exocytosis ( Atlas et al. 2003) and (iv) a putative functional coupling between the pore of the calcium channel and syntaxin 1A ( Wiser et al. Owing to: (i) the functional coupling of VGCC to exocytotic proteins (ii) the selective binding of Sr 2+ and Ba 2+ to Ca 2+ channels (iii) the poor affinity of Sr 2+ and Ba 2+ for the various synaptotagmin isoforms ( Li et al. This outcome demonstrates a link between the ion permeation pore of the channel and syntaxin 1A, suggesting that ions occupying the pore of the channel could coordinate the cross-talk between the channel and the exocytotic machinery ( Wiser et al. Ba 2+) variously alter the cardiac Ca V1.2 (Lc-type) Ca 2+ channel interaction with syntaxin 1A ( Wiser et al. Characterization of functional interactions between VGCC and synaptic proteins showed that different charge carriers (Ca 2+ vs. 2004), and to generate a unique functional exocytotic unit, termed the ‘excitosome’ ( Wiser et al.
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On the other hand, another Ca 2+ binding protein, the VGCC, has been shown to be functionally and physically coupled to various exocytotic proteins ( Sheng et al. Various synaptotagmin isoforms that bind phospholipids in a Ca 2+-dependent manner have been proposed to be the most likely Ca 2+ sensors of the release process ( Rizo and Sudhof 1998 Chapman 2002 Yoshihara and Littleton 2002). Depolarization-induced secretion is supported by other divalent ions, such as Sr 2+ or Ba 2+, which generate characteristic inward currents and raise their intracellular concentrations similarly to Ca 2+. The short latency between Ca 2+ influx and transmitter release suggests a close apposition of the Ca 2+ source, a voltage-gated Ca 2+ channel (VGCC), and the exocytotic machinery ( Stanley 1997 Catterall 1998 Atlas 2001 Fisher and Bourque 2001 Jarvis and Zamponi 2005). It challenges the conventional view that intracellular Ca 2+ ion build-up via VGCC permeation is required to trigger secretion and establishes the VGCC as a plausible Ca 2+ sensor protein in the process of neuroendocrine secretion.įast Ca 2+-dependent depolarization-induced transmitter release is one of the most intriguing forms of secretion ( Katz and Miledi 1967). Our model allows for a tight temporal and spatial coupling between the excitatory stimulation event and vesicle fusion. These results provide strong evidence that occupancy of the pore of the channel by an impermeable cation leads to a conformational change that is transmitted to the exocytotic machinery upstream of intracellular cation build-up (intracellular Ca 2+ concentration). La 3+ inward currents were not detected and the highly sensitive La 3+/fura-2 imaging assay (∼1 p m) detected no La 3+ entry, cytosolic La 3+ build-up, or alterations in cytosolic Ca 2. Lanthanide efficacy was stringently dependent on ionic radius with La 3+ > Ce 3+ > Pr 3+, consistent with a size-selective binding interface of trivalent cations at the channel pore. Cd 2+, nifedipine, or verapamil inhibited depolarization-evoked secretion in La 3+, indicating specific binding of La 3+ at the pore of L-type VGCC, probably at the poly-glutamate (EEEE) locus. We found that replacing Ca 2+ with La 3+ or other lanthanide ions supported exocytosis in divalent ion-free solution. To explore this possibility we have examined catecholamine secretion in PC12 and chromaffin cells. The coupling of voltage-gated Ca 2+ channel (VGCC) to exocytotic proteins suggests a regulatory function for the channel in depolarization-evoked exocytosis.