Calmodulin bifurcates the local Ca2+ signal that modulates P/Q-type Ca2+ channels.
Acute modulation of P/Q-type (alpha1A) calcium channels by neuronal activity-dependent changes in intracellular Ca2+ concentration may contribute to short-term synaptic plasticity, potentially enriching the neurocomputational capabilities of the brain. An unconventional mechanism for such channel modulation has been proposed in which calmodulin (CaM) may exert two opposing effects on individual channels, initially promoting ('facilitation') and then inhibiting ('inactivation') channel opening. Here we report that such dual regulation arises from surprising Ca2+-transduction capabilities of CaM. First, although facilitation and inactivation are two competing processes, both require Ca2+-CaM binding to a single 'IQ-like' domain on the carboxy tail of alpha1A; a previously identified 'CBD' CaM-binding site has no detectable role. Second, expression of a CaM mutant with impairment of all four of its Ca2+-binding sites (CaM1234) eliminates both forms of modulation. This result confirms that CaM is the Ca2+ sensor for channel regulation, and indicates that CaM may associate with the channel 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 channel inactivation, whereas Ca2+ sensing by the carboxy-terminal lobe induces facilitation. Such lobe-specific detection provides a compact means to decode local Ca2+ signals in two ways, and to separately initiate distinct actions on a single molecular complex.
DeMaria
C D
CD
The Johns Hopkins University School of Medicine, Departments of Biomedical Engineering and Neuroscience, Program in Molecular and Cellular Systems Physiology, 720 Rutland Avenue, Baltimore, Maryland 21205, USA.
Soong
T W
TW
Alseikhan
B A
BA
Alvania
R S
RS
Yue
D T
DT
D000595:Amino Acid Sequence; D002118:Calcium / Q000378:metabolism*; D020865:Calcium Channels, P-Type / Q000378:metabolism*; D020907:Calcium Channels, Q-Type / Q000378:metabolism*; D020013:Calcium Signaling; D002147:Calmodulin / Q000378:metabolism*; D002460:Cell Line; D006801:Humans; D008969:Molecular Sequence Data; D011994:Recombinant Proteins / Q000378:metabolism
D020865:Calcium Channels, P-Type; D020907:Calcium Channels, Q-Type; D002147:Calmodulin; D011994:Recombinant Proteins; D002118:Calcium