Important Contribution of α-Neurexins to Ca²⁺-Triggered Exocytosis of Secretory Granules

Abstract

␣-Neurexins constitute a family of neuronal cell surface molecules that are essential for efficient neurotransmission, because mice lacking two or all three ␣-neurexin genes show a severe reduction of synaptic release. Although analyses of ␣-neurexin knock-outs and transgenic rescue animals suggested an involvement of voltage-dependent Ca 2ϩ channels, it remained unclear whether ␣-neurexins have a general role in Ca 2ϩ -dependent exocytosis and how they may affect Ca 2ϩ channels. Here we show by membrane capacitance measurements from melanotrophs in acute pituitary gland slices that release from endocrine cells is diminished by Ͼ50% in adult ␣-neurexin double knock-out and newborn triple knock-out mice. There is a reduction of the cell volume in mutant melanotrophs; however, no ultrastructural changes in size or intracellular distribution of the secretory granules were observed. Recordings of Ca 2ϩ currents from melanotrophs, transfected human embryonic kidney cells, and brainstem neurons reveal that ␣-neurexins do not affect the activation or inactivation properties of Ca 2ϩ channels directly but may be responsible for coupling them to release-ready vesicles and metabotropic receptors. Our data support a general and essential role for ␣-neurexins in Ca 2ϩ -triggered exocytosis that is similarly important for secretion from neurons and endocrine cells.

Modulation of synaptic function through the α-neurexin–specific ligand neurexophilin-1

“…It is important to note, however, that our results do not imply that GABA A R or GABA B R at inhibitory synapses are an exclusive target of Nxph1/α−Nrxn. In fact, we reported previously that the GABA B R-mediated modulation of Ca V 2.2 channels, required for its effect on vesicle release (58), was also impaired at excitatory brainstem synapses of α-Nrxn KO mice (45). Even more importantly, α-Nrxn is abundantly expressed in glutamatergic neurons as well (12) and has unequivocal effects on release from excitatory synapses (9,44,46,78).…”

“…In addition, research has identified several molecules, mostly ion channels and receptors, which are functionally impaired when Nrxn expression is altered. Nrxn variants have been found to affect voltage-dependent calcium channels (9,10), GABA A R (7, 37), NMDAR (44), GABA B R (36,45), nicotinergic acetylcholine receptors (69), and AMPAR (47). These ionotropic and metabotropic receptors represent "target molecules" of Nrxn that may include some physical association, but it appears unlikely that the functional link to all these requires stable protein-protein interactions.…”

Nicotinic Acetylcholine Receptor Alterations in Autism Spectrum Disorders – Biomarkers and Therapeutic Targets

“…Neurexin 1/2/3-triple knock-out animals die perinatally and have reduced spontaneous and evoked neurotransmission at glutamatergic and GABAergic synapses, demonstrating that -neurexins are necessary for neurotransmitter release at synapses (Missler et al, 2003). Additionally, mice lacking neurexins have impaired neuroendocrine secretion (Dudanova et al, 2006), which may mirror some children with autism that exhibit dysfunction of the hypothalamic-pituitary-adrenocortical system, possibly due to altered neuroendocrine regulation (Corbett et al, 2006). Similar to the neurexin triple knockout animals, mice lacking neurexin1/2 or neurexin2/3 die within 1 month after birth and have reduced neurotransmission.…”

Polarized Targeting of Neurexins to Synapses Is Regulated by their C-Terminal Sequences

“…Therefore, understanding their targeting to presynaptic and postsynaptic compartments appears mandatory. Nrxns exist and function predominantly at the presynaptic terminal (Ushkaryov et al, 1992;Dean et al, 2003;Missler et al, 2003;Graf et al, 2004;Dudanova et al, 2006;Berninghausen et al, 2007;Li et al, 2007;Taniguchi et al, 2007), although a small but relevant population at the postsynapse is possible (Kattenstroth et al, 2004;Taniguchi et al, 2007). Neuroligins are present almost exclusively at the postsynaptic compartment (Ichtchenko et al, 1995;Song et al, 1999;Scheiffele et al, 2000;Varoqueaux et al, 2006;Berninghausen et al, 2007).…”