Neuronal Ca2+ channels are key transducers coupling excitability to cellular function. As such, they are tightly regulated by multiple G protein-signaling pathways that finely tune their activity. In addition to fast, direct Gβγ modulation of Ca2+ channels, a slower Gαq/11-mediated mechanism has remained enigmatic despite intensive study. Recent work suggests that membrane phosphoinositides are crucial determinants of Ca2+ channel activity. Here, we discuss their role in Ca2+ channel modulation and the leading theories that seek to elucidate the underlying molecular details of the so-called "mysterious" Gq/11-mediated signal.
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