Ca2+/calmodulin binds to and modulates P/Q-type calcium channels

Abstract

Neurotransmitter release at many central synapses is initiated by an influx of calcium ions through P/Q-type calcium channels, which are densely localized in nerve terminals. Because neurotransmitter release is proportional to the fourth power of calcium concentration, regulation of its entry can profoundly influence neurotransmission. N- and P/Q-type calcium channels are inhibited by G proteins, and recent evidence indicates feedback regulation of P/Q-type channels by calcium. Although calcium-dependent inactivation of L-type channels is well documented, little is known about how calcium modulates P/Q-type channels. Here we report a calcium-dependent interaction between calmodulin and a novel site in the carboxy-terminal domain of the alpha1A subunit of P/Q-type channels. In the presence of low concentrations of intracellular calcium chelators, calcium influx through P/Q-type channels enhances channel inactivation, increases recovery from inactivation and produces a long-lasting facilitation of the calcium current. These effects are prevented by overexpression of a calmodulin-binding inhibitor peptide and by deletion of the calmodulin-binding domain. Our results reveal an unexpected association of Ca2+/calmodulin with P/Q-type calcium channels that may contribute to calcium-dependent synaptic plasticity.

Systematic Identification of Splice Variants in Human P/Q-Type Channel α12.1 Subunits: Implications for Current Density and Ca2+-Dependent Inactivation

“…As a first step in defining the potentially broader spectrum of functional sequelae, we focused on novel splice variations in the ␣ 1A C-terminal tail, because this region contains critical structural determinants for Ca 2ϩ feedback regulation of corresponding channels. In particular, Ca 2ϩ /CaM binding to an IQ-like binding motif in exon 40 , or possibly to a CBD binding motif in exon 42 (Lee et al, 1999, initiates both channel facilitation and inactivation by Ca 2ϩ . The proximity of these structures to exons 43 and 44 (Figs.…”

Interactions with PDZ Proteins Are Required for L-Type Calcium Channels to Activate cAMP Response Element-Binding Protein-Dependent Gene Expression

“…Dolmetsch et al (2001) found that removal of the CaM-binding "IQ motif" from ␣ 1C produces L-type calcium channels incapable of signaling to CREB, demonstrating an inherent prerequisite within the channel for activation of CRE-dependent transcription. Yet various calcium channel ␣ 1 subunits, not just ␣ 1C , contain similar (or identical) IQ motifs and interact with CaM (Lee et al, 1999;Peterson et al, 1999). Thus, another mechanism must provide L-type calcium channels with a "private line" to the nucleus, allowing only these voltage-gated calcium channels to trigger CREB phosphorylation.…”

Short-Term Presynaptic Plasticity

“…Multiple calcium-sensing proteins, including calmodulin, calcium-binding protein-1, and visinin-like protein-2, can interact with calcium channels and mediate use-dependent changes in presynaptic calcium entry (Lee et al 1999(Lee et al , 2002Peterson et al 1999;Lautermilch et al 2005). Presynaptic recordings from the calyx of Held have shown that prolonged high-frequency stimulation reduces calcium entry ) that can contribute to depression.…”