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- Title
Ion interaction at the pore of Lc-type Ca<sup>2+</sup> channel is sufficient to mediate depolarization-induced exocytosis.
- Authors
Lerner, Immanuel; Trus, Michael; Cohen, Roy; Yizhar, Ofer; Nussinovitch, Itzhak; Atlas, Daphne
- Abstract
The coupling of voltage-gated Ca2+ channel (VGCC) to exocytotic proteins suggests a regulatory function for the channel in depolarization-evoked exocytosis. To explore this possibility we have examined catecholamine secretion in PC12 and chromaffin cells. We found that replacing Ca2+ with La3+ or other lanthanide ions supported exocytosis in divalent ion-free solution. Cd2+, nifedipine, or verapamil inhibited depolarization-evoked secretion in La3+, indicating specific binding of La3+ at the pore of L-type VGCC, probably at the poly-glutamate (EEEE) locus. Lanthanide efficacy was stringently dependent on ionic radius with La3+ > Ce3+ > Pr3+, consistent with a size-selective binding interface of trivalent cations at the channel pore. La3+ inward currents were not detected and the highly sensitive La3+/fura-2 imaging assay (∼1 pm) detected no La3+ entry, cytosolic La3+ build-up, or alterations in cytosolic Ca2. 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 Ca2+ concentration). Our model allows for a tight temporal and spatial coupling between the excitatory stimulation event and vesicle fusion. It challenges the conventional view that intracellular Ca2+ ion build-up via VGCC permeation is required to trigger secretion and establishes the VGCC as a plausible Ca2+ sensor protein in the process of neuroendocrine secretion.
- Subjects
EXOCYTOSIS; PROTEINS; CATECHOLAMINES; CHROMAFFIN cells; IONS; CELL physiology
- Publication
Journal of Neurochemistry, 2006, Vol 97, Issue 1, p116
- ISSN
0022-3042
- Publication type
Article
- DOI
10.1111/j.1471-4159.2006.03709.x