1. 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
2. National Neuroscience Institute, 11 Jalan Tan Tuck Seng, Singapore 308433, and Department of Physiology, National University of Singapore

Correspondence to: David T. Yue¹ Correspondence and requests for materials should be addressed to D.T.Y. (e-mail: Email: dyue@bme.jhu.edu).

Abstract

Acute modulation of P/Q-type (_1A) calcium channels by neuronal activity-dependent changes in intracellular Ca²⁺ concentration may contribute to short-term synaptic plasticity^{1, 2, 3}, potentially enriching the neurocomputational capabilities of the brain^{4, 5}. An unconventional mechanism for such channel modulation has been proposed^{6, 7} 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 _1A⁸; a previously identified 'CBD' CaM-binding site^{6, 7} 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.