G-protein- and cAMP-dependent L-channel gating modulation: a manyfold system to control calcium entry in neurosecretory cells.
Voltage-gated Ca2+ channels are crucial to the control of Ca2+ entry in neurosecretory cells. In the chromaffin cells of adrenal medulla, paracrinally or autocrinally released neurotransmitters induce profound changes in Ca2+ channel gating and Ca2+-dependent events controlling catecholamine secretion and cell activity. The generally held view of these processes is that neurotransmitter-induced modulation of the most widely expressed Ca2+ channels in these cells (N-, P/Q- and L-type) follows two distinct pathways: a direct membrane-delimited Gi/o-protein-induced inhibition of N- and P/Q-type and a remote cAMP-mediated facilitation of L-channels. Both actions depend on voltage, although with remarkably different molecular and kinetic aspects. Recent findings, however, challenge this simple scheme and suggest that L-channels do not require strong pre-pulses to be recruited or facilitated. They are available during normal depolarizations and may be tonically inhibited by Gi/o proteins activated by the released neurotransmitters. Like the N- and P/Q-channels, this autocrine modulation is localized to membrane microareas. Unlike N- and P/Q-channels, however, the inhibition of L-channels is largely independent of voltage and develops in parallel with cAMP-mediated potentiation of channel gating. As L-channels play a crucial role in the control of catecholamine release in chromaffin cells, the two opposite modulations mediated by Gi/o proteins and cAMP may represent an effective way to broaden the dynamic range of Ca2+ signals controlling exocytosis. Here, we review the basic features of this novel L-type channel inhibition comparing it to the well-established forms of L-channel potentiation and voltage-dependent facilitation.
Carbone
E
E
Dipartimento di Neuroscienze, Unità di Ricerca INFM, Torino, Italy. emilio.carbone@unito.it
Carabelli
V
V
Cesetti
T
T
Baldelli
P
P
Hernández-Guijo
J M
JM
Giusta
L
L
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000187:drug effects / Q000502:physiology*; D002462:Cell Membrane / Q000502:physiology; D019439:Chromaffin Cells / Q000502:physiology; D000242:Cyclic AMP / Q000494:pharmacology*; D004594:Electrophysiology; D019204:GTP-Binding Proteins / Q000502:physiology*; D006801:Humans; D015640:Ion Channel Gating; D009490:Neurosecretory Systems / Q000378:metabolism*
D020746:Calcium Channels, L-Type; D000242:Cyclic AMP; D019204:GTP-Binding Proteins; D002118:Calcium