Calmodulin bifurcates the local Ca2+ signal that modulates P/Q-type Ca2+ channels

Acute modulation of P/Q-type (alpha (1A)) calcium channels by neuronal acti vity-dependent changes in intracellular Ca2+ concentration may contribute t o short-term synaptic plasticity(1-3), potentially enriching the neurocompu tational capabilities of the brain(4,5). An unconventional mechanism for su ch channel modulation has been proposed(6,7) in which calmodulin (CaM) may exert two opposing effects on individual channels, initially promoting ('fa cilitation') and then inhibiting ('inactivation') channel opening. Here we report that such dual regulation arises from surprising Ca2+-transduction c apabilities of CaM. First, although facilitation and inactivation are two c ompeting processes, both require Ca2+-CaM binding to a single 'IQ-like' dom ain on the carboxy tail of alpha (8)(1A); a previously identified 'CBD' CaM -binding site(6,7) has no detectable role. Second, expression of a CaM muta nt with impairment of all four of its Ca2+-binding sites (CaM1234) eliminat es both forms of modulation. This result confirms that CaM is the Ca2+ sens or for channel regulation, and indicates that CaM may associate with the ch annel even before local Ca2+ concentration rises. Finally, the bifunctional capability of CaM arises from bifurcation of Ca2+ signalling by the lobes of CaM: Ca2+ binding to the amino-terminal lobe selectively initiates chann el inactivation, whereas Ca2+ sensing by the carboxy-terminal lobe induces facilitation. Such lobe-specific detection provides a compact means to deco de local Ca2+ signals in two ways, and to separately initiate distinct acti ons on a single molecular complex.