β-Neuregulin-1 is required for the in vivo development of functional Ca(2+)-activated K(+) channels in parasympathetic neurons

The development of functional Ca(2+)-activated K(+) channels (K(Ca)) in chick ciliary ganglion (CG) neurons requires interactions with afferent preganglionic nerve terminals. Here we show that the essential preganglionic differentiation factor is an isoform of β-neuregulin-1. β-Neuregulin-1 transcripts are expressed in the midbrain preganglionic Edinger–Westphal nucleus at developmental stages that coincide with or precede the normal onset of macroscopic K(Ca) in CG neurons. Injection of β-neuregulin-1 peptide into the brains of developing embryos evoked a robust stimulation of functional K(Ca) channels at stages before the normal appearance of these channels in CG neurons developing in vivo. Conversely, injection of a neutralizing antiserum specific for β-neuregulin-1 inhibited the development of K(Ca) channels in CG neurons. Low concentrations of β-neuregulin-1 evoked a robust increase in whole-cell K(Ca) in CG neurons cocultured with iris target tissues. By contrast, culturing CG neurons with iris cells or low concentrations of β-neuregulin-1 by themselves was insufficient to stimulate K(Ca). These data suggest that the preganglionic factor required for the development of K(Ca) in ciliary ganglion neurons is an isoform of β-neuregulin-1, and that this factor acts in concert with target-derived trophic molecules to regulate the differentiation of excitability.