Voltage-dependent calcium channels at the plasma membrane, but not vesicular channels, couple exocytosis to endocytosis.
Although calcium influx triggers endocytosis at many synapses and non-neuronal secretory cells, the identity of the calcium channel is unclear. The plasma membrane voltage-dependent calcium channel (VDCC) is a candidate, and it was recently proposed that exocytosis transiently inserts vesicular calcium channels at the plasma membrane, thus triggering endocytosis and coupling it to exocytosis, a mechanism suggested to be conserved from sea urchin to human. Here, we report that the vesicular membrane, when inserted into the plasma membrane upon exocytosis, does not generate a calcium current or calcium increase at a mammalian nerve terminal. Instead, VDCCs at the plasma membrane, including the P/Q-type, provide the calcium influx to trigger rapid and slow endocytosis and, thus, couple endocytosis to exocytosis. These findings call for reconsideration of the vesicular calcium channel hypothesis. They are likely to apply to many synapses and non-neuronal cells in which VDCCs control exocytosis, and exocytosis is coupled to endocytosis.
National Institute of Neurological Disorders and Stroke, Bethesda, MD 20892, USA.
Lei
L
Xue
Zhen
Z
Zhang
Benjamin D
BD
McNeil
Fujun
F
Luo
Xin-Sheng
XS
Wu
Jiansong
J
Sheng
Wonchul
W
Shin
Ling-Gang
LG
Wu
D000595:Amino Acid Sequence; D000818:Animals; D001905:Botulinum Toxins / Q000494:pharmacology; D015220:Calcium Channels / Q000737:chemistry / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism*; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D004705:Endocytosis / Q000187:drug effects; D005089:Exocytosis / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects; D008561:Membrane Fusion / Q000187:drug effects; D008969:Molecular Sequence Data; D009411:Nerve Endings / Q000187:drug effects / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D013572:Synaptic Vesicles / Q000187:drug effects / Q000378:metabolism*
D015220:Calcium Channels; D004533:Egtazic Acid; D001905:Botulinum Toxins; C025603:1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid