Of capturing fish, mobilizing enzymes, and a surprising source for serotonin

This month's installment of Generally Physiological considers a nonconven-tional mechanism of serotonin release in the dorsal raphe nucleus, the use of insulin by fish-hunting cone snails to induce hypoglycemic shock in their prey, and how the heat of catalysis might enhance enzyme diffusion. Extracellular serotonin acts through somatodendritic 5-HT1A autorecep-tors to suppress the activity of sero-tonergic neurons of the dorsal raphe nucleus through an autoinhibitory negative feedback mechanism. The concentration of this pool of extra-cellular serotonin increases when its reuptake is inhibited by the well-known class of antidepressants known as selective serotonin reuptake inhib-itors, suggesting that there is ongoing release of serotonin into the extra-cellular space. Using 5-HT1A auto-receptor-activated GIRK currents of patched serotonergic neurons to assay extracellular serotonin in rat brain slices, and suppression of firing rate to evaluate its autoinhibitory activity , in this issue Mlinar et al. now show, that, remarkably, autoinhibi-tory serotonin release appears to occur through a nonexocytotic mechanism. Release persisted despite inhibition of serotonin uptake into synaptic vesicles (a manipulation that suppressed serotonergic inhibitory postsynaptic potentials), calcium influx , neuronal firing, or plasma membrane transporters (to rule out efflux through reverse transport). Mlinar et al. (2015) thus conclude that the release of serotonin mediating auto-inhibition occurs from a nonvesicular pool through a nonexocytotic mechanism and propose that it arises instead from simple diffusion across the plasma membrane. The predatory marine cone snails are known for the astonishing diversity of their venom peptides, with the venom of individual Conus species containing a complex mixture of numerous peptides, and different species producing venom of distinct composition. Most of the known conopeptides are neurotoxins that specifically target channels, receptor , or transporters, proving almost as useful to neuroscientists as to cone snails. In a marked departure from this scheme, however, Safavi-Hemami et al. (2015) identified specialized forms of the peptide hormone insulin in the venom of two fish-hunting cone snails, Conus geo­ graphus and Conus tulipa. Analysis of the C. geographus venom gland tran-scriptome revealed two insulin-like transcripts (Con-Ins G1 and Con-Ins G2), with the predicted mature Con-Ins G1 peptide resembling ver-tebrate—specifically fish—insulin. RT-PCR analysis confirmed the presence in the venom gland of insulin-like transcripts, and MS analysis showed that Con-Ins G1 and variant peptides were abundant in C. geogra­ phus venom. C. geographus uses a " net-hunting " strategy to capture fish, engulfing them in a false mouth before paralyzing them, and the venom gland of …