Voltage Dependence of a Neuromodulator-Activated Ionic Current

Abstract

The neuromodulatory inward current (IMI) generated by crab Cancer borealis stomatogastric ganglion neurons is an inward current whose voltage dependence has been shown to be crucial in the activation of oscillatory activity of the pyloric network of this system. It has been previously shown that IMI loses its voltage dependence in conditions of low extracellular calcium, but that this effect appears to be regulated by intracellular calmodulin. Voltage dependence is only rarely regulated by intracellular signaling mechanisms. Here we address the hypothesis that the voltage dependence of IMI is mediated by intracellular signaling pathways activated by extracellular calcium. We demonstrate that calmodulin inhibitors and a ryanodine antagonist can reduce IMI voltage dependence in normal Ca2+, but that, in conditions of low Ca2+, calmodulin activators do not restore IMI voltage dependence. Further, we show evidence that CaMKII alters IMI voltage dependence. These results suggest that calmodulin is necessary but not sufficient for IMI voltage dependence. We therefore hypothesize that the Ca2+/calmodulin requirement for IMI voltage dependence is due to an active sensing of extracellular calcium by a GPCR family calcium-sensing receptor (CaSR) and that the reduction in IMI voltage dependence by a calmodulin inhibitor is due to CaSR endocytosis. Supporting this, preincubation with an endocytosis inhibitor prevented W7 (N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide hydrochloride)-induced loss of IMI voltage dependence, and a CaSR antagonist reduced IMI voltage dependence. Additionally, myosin light chain kinase, which is known to act downstream of the CaSR, seems to play a role in regulating IMI voltage dependence. Finally, a Gβγ-subunit inhibitor also affects IMI voltage dependence, in support of the hypothesis that this process is regulated by a G-protein-coupled CaSR.

Circuit Robustness to Temperature Perturbation Is Altered by Neuromodulators

“…Proctolin and oxotemorine activate a current called I MI which is a voltage-dependent inward current that is blocked by extracellular Ca 2+ (Golowasch and Marder, 1992b; Gray et al, 2017; Gray and Golowasch, 2016; Swensen and Marder, 2000, 2001). I MI ‘s voltage-dependence makes it ideally suited to enhance oscillations (Sharp et al, 1993) because it provides an additional inward current at more depolarized membrane potentials and is blocked at the trough of the oscillation.…”

Rapid adaptation to elevated extracellular potassium in the pyloric circuit of the crab, Cancer borealis

“…preparations in which neuromodulatory inputs are removed initially lose rhythmicity and gradually recover over the course of several days Simmers, 1998, 2002;Gray and Golowasch, 2016;Gray et al, 2017).…”

The complexity of small circuits: the stomatogastric nervous system

“…In particular, they all activate the same modulator-activated inward current (I MI ) [27] (Fig. 2C) which shows unusual voltage-dependence in that it is regulated by both intra- and extracellular calcium [28]. This single current represents a powerful way to activate the pyloric circuit [29], and recent experimental and theoretical work shows that just the negative slope conductance of its IV curve is sufficient to elicit oscillatory activity [30,31].…”