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

Abstract

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.

A novel locus for episodic ataxia:UBR4 the likely candidate

“…Calmodulin has its role in calcium signaling through calciumdependent inactivation or calcium-dependent facilitation. 38,39 It has been shown to bind and act as a regulator of neural excitability in KCNQ 40 and Cav2.1 channels (see Halling et al for a recent review 41 ). The CACNA1A gene encodes the Cav2.1 channel, and it is mutations in this gene that cause the most common form of EA (EA2).…”

Presynaptic inhibition of spontaneous acetylcholine release induced by adenosine at the mouse neuromuscular junction

“…However, further investigations are needed to clarify whether AD induces presynaptic inhibition of P/Qtype VDCCs by a mechanism that involves calmodulin. It has been found that Ca 2 þ -calmodulin may exert two opposing effects on P/Q-type VDCCs, initially facilitating and then inactivating channel opening (Lee et al, 2000;DeMaria et al, 2001). …”

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

“…The analogous EF-hand motif in ␣ 1 1.2 is essential for its CDI (DeLeon et al, 1995;Zuhlke and Reuter, 1998;Peterson et al, 2000), but the motif probably transduces CDI rather than binds Ca 2ϩ (Peterson et al, 2000). Instead, the trigger for Ca 2ϩ regulation of either ␣ 1 1.2 or ␣ 1 2.1 is Ca 2ϩ /CaM interaction with a distinct IQ-like region (Peterson et al, 1999;Qin et al, 1999;Zuhlke et al, 1999;DeMaria et al, 2001). Hence, there is reason to wonder whether EF-hand splicing could alter Ca 2ϩ regulation of P/Qtype channels (Bourinet et al, 1999;Chaudhuri et al, 2001).…”

“…In the local domain regimen, this rate constant would be a function of [Ca 2ϩ ] domain and P o , where P o is the peak open probability of unfacilitated channels at ϩ10 mV. Specifically, the strength of CDF ( g ) should be closely proportional to P o ϫ [Ca 2ϩ ] domain 2 , where the square term reflects triggering of CDF by two Ca 2ϩ ions binding to the C-terminal lobe of CaM (Peterson et al, 1999;DeMaria et al, 2001). Considering that [Ca 2ϩ ] domain ϰ i, we have that g ϰ P o i 2 .…”