Inhibitory modulation by FMRFamide of the voltage‐gated sodium current in identified neurones in Lymnaea stagnalis.

Abstract

SUMMARY1. The putative neurotransmitter FMRFa (Phe-Met-Arg-Phe-amide) caused an inhibitory modulation of the voltage-gated sodium current (INa) in central neurones, the peptidergic caudo dorsal cells (CDCs) of the mollusc Lymnaea stagnal7is. FMRFa reduced INa at all command potentials tested (ranging from -35 to + 20 mV), but the amplitude of the effect of FMRFa was voltage dependent, inhibition being stronger at more negative potentials (50 + 5 % reduction at half-maximal INa activation versus 25 + 8 % at the peak of the I-V curve).2. INa current traces were well fitted by a Hodgkin & Huxley based model, using m3 activation kinetics and two time constants for inactivation.3. The steady-state inactivation curve of INa was characterized by half-maximal inactivation at -42-5 + 1-81 mV and a slope factor of 4-6 + 0-28 mV. The fastest time constant of inactivation ran from 100 + 5 to 0-8 + 0-32 ms and the slower time constant from 505 +45 to 4-8 + 1-40 ms in the range -40 to -5 mV.4. FMRFa had no significant effect on either component of inactivation, nor on the voltage dependence of steady-state inactivation, nor on the maximal conductance.5. FMRFa affected the activation of INa. The activation time constant was increased, ranging from 0-75 + 0-050 to 0-22 + 0-017 ms under control and from 0-91 + 0 043 to 0-31 + 0-038 ms with FMRFa in the voltage range -25 to + 5 mV. The steady-state activation curve was shifted to less negative potentials: half-maximal activation occurred at -26-5 + 1-2 mV under control and at 23-6 + 1-4 mV with FMRFa; the slope factor (4-6 + 1-4 mV in control experiments) was not affected. The combination of slower activation kinetics and a shift in the voltage dependence of activation in the Hodgkin & Huxley based model, adequately explained the reduction of INa by FMRFa.

Inhibition of a slowly inactivating high-voltage-activated calcium current by the neuropeptide FMRFa in molluscan neuroendocrine cells

“…and occurs at low concentrations (EDs0 = 7 x 10 -9 M) (Brussaard et al, 1988). These three characteristics are strikingly similar to those of the suppression of the sustained calcium current and contrast with the desensitization and slow recovery of the other responses to FMRFa (Brussaard et al, 1988(Brussaard et al, , 1990(Brussaard et al, , 1991aVeerman and Kits, unpublished). Therefore, it is likely that FMRFa suppresses the excitability of the CDCs via the selective inhibition of the sustained calcium current.…”

“…FMRFa inhibits CDCs by simultaneous inhibition of the voltage-activated sodium current (Brussaard et al, 1990(Brussaard et al, , 1991a, activation of a potassium current (Brussaard et al, 1988;Veerman and Kits, unpublished) and suppression of the sustained HVA calcium current (this paper). Since it was previously concluded on the basis of structure-activity studies that the multiple responses to FMRFa are mediated by a single receptor type (Brussaard et al, 1989) and that activation of the potassium current by FMRFa proceeds via the arachidonic acid pathway (Veerman and Kits, unpublished), the divergence of the FMRFa responses may occur at the level of the G-protein subtype or the primary effector of the G-protein.…”

“…These effects of FMRFa are independent, but mediated through a single FMRFa receptor type (Brussaard et al, 1988(Brussaard et al, , 1989. Voltage-clamp recordings demonstrated that FMRFa activates a potassium current (Veerman and Kits, unpublished) and inhibits the voltage-dependent sodium current (Brussaard et al, 1990(Brussaard et al, , 1991a. In addition, it was suggested that FMRFa inhibits the voltage-dependent calcium current (Brussaard et al, 1990).…”

Dopaminergic Modulation of Sodium Current in Hippocampal Neurons via cAMP-Dependent Phosphorylation of Specific Sites in the Sodium Channel α Subunit

“…Na ϩ currents in Aplysia neurons are modulated by the peptide FMRFamide (Brussaard et al, 1991), but the mechanism of receptor coupling to Na ϩ channel modulation is unknown. Consistent with the present results in hippocampal neurons, activation of dopaminergic receptors modulates whole-cell Na ϩ current in neostriatal neurons via a PKAdependent signaling pathway (Surmeier et al, 1992;Schiffmann et al, 1995).…”

Dopamine D1 receptor modulates the voltage‐gated sodium current in rat striatal neurones through a protein kinase A.

“…Because voltage-gated sodium channels are responsible for the initiation and propagation of the action potential (Eccles, 1964), modulation of their activity is expected to affect dramatically neuronal excitability. In different cellular preparations, activation of the ,-adrenergic (Schubert, Vandongen, Kirsch & Brown, 1989), thyrotropin-releasing hormone (Lopez-Barneo, Castellano & Toledo-Aral, 1990), dopamine (Surmeier et al 1992) and FMRFamide receptors (Brussaard, Lodder, Ter Maat, de Vlieger & Kits, 1991) have been reported to modulate a voltage-gated sodium current. However, the transduction mechanisms involved in all of these neurotransmitter effects remains largely unknown.…”