Intracellular Ca²⁺ release‐dependent inactivation of Ca²⁺ currents in thalamocortical relay neurons

Abstract

Neuronal Ca(2+) channels are rapidly inactivated by a mechanism that is termed Ca(2+)-dependent inactivation (CDI). In this study we investigated the influence of intracellular Ca(2+) release on CDI of high-voltage-activated Ca(2+) channels in rat thalamocortical relay neurons by combining voltage-clamp, Ca(2+) imaging and immunological techniques. Double-pulse protocols revealed CDI, which depended on the length of the conditioning pulses. Caffeine caused a concentration-dependent increase in CDI that was accompanied by an increase in the duration of Ca(2+) transients. Inhibition of ryanodine receptors and endoplasmic Ca(2+) pumps (by thapsigargin or cyclopiazonic acid) resulted in a reduction of CDI. In contrast, inhibition of inositol 1,4,5-tris-phosphate receptors by intracellular application of 2-aminoethoxy diphenyl borate or heparin did not influence CDI. The block of transient receptor potential channels by extracellular application of 2-aminoethoxy diphenyl borate, however, resulted in a significant reduction of CDI. The central role of L-type Ca(2+) channels was emphasized by the near-complete block of CDI by nifedipine, an effect only surpassed when Ca(2+) was replaced by Ba(2+) and chelated by 1,2-bis(o-aminophenoxy)ethane-N,N,N',N',-tetraacetic acid (BAPTA). Trains of action potential-like stimuli induced a strong reduction in high-voltage-activated Ca(2+) current amplitude, which was significantly reduced when intracellular Ca(2+) stores were made inoperative by thapsigargin or Ba(2+)/BAPTA. Western blotting revealed expression of L-type Ca(2+) channels in thalamic and hippocampal tissue but not liver tissue. In summary, these results suggest a cross-signalling between L-type Ca(2+) channels and ryanodine receptors that controls the amount of Ca(2+) influx during neuronal activity.

Central Nervous System–Toxic Lidocaine Concentrations Unmask L-Type Ca2+ Current–Mediated Action Potentials in Rat Thalamocortical Neurons: An In Vitro Mechanism of Action Study

“…However, the net level of [Ca 2+ ] i increases in ventrobasal TC relay neurons in humans in vivo is unknown and will also depend on whether lidocaine affects other regulatory mechanisms of Ca 2+ homeostasis, such as Ca 2+ -induced Ca 2+ release, Ca 2+ -dependent inactivation, and functioning of the Na + -Ca 2+ exchanger. 35,[49][50][51] For example, Xu et al 22 reported that lidocaine inhibits KCl-and carbachol-evoked intracellular Ca 2+ transients in a concentration range similar to that in our study (0.1-2.3 mM), albeit in a neuronal cell culture. Clearly, further research, including studies using Figure 5.…”

The monoterpene (–)‐carvone: A novel agonist of TRPV1 channels

“…To investigate whether the [Ca 21 ] i transients induced by (-)-Cv resulted from calcium release of intracellular stores, DRG neurons were bathed in calcium-free KRH. A caffeine (3 mM) and thapsigargin (1 lM) solution was used to induce internal calcium release (17,18). While (-)-Cv (1 mM) in the absence of extracellular calcium was not able to cause any fluorescence change in these conditions, [Ca 21 ] i transients were observed following application of caffeine plus thapsigargin solution (Fig.…”

Kisspeptin Inhibits High-Voltage Activated Ca²⁺ Channels in GnRH Neurons via Multiple Ca²⁺ Influx and Release Pathways

“…However, the inhibition may be similar to the inhibition by caffeine of L-type VGCCs in thalamocortical relay neurons [54]. Rankovic et al [54] suggested that, as in cardiac myocytes, the coupling between L-type VGCCs and RyRs in thalamocortical neurons occurs in a confined area where a cluster of RyRs is juxtaposed with a group of L-type VGCCs, forming a ‘Ca 2+ release unit’.…”

“…However, the inhibition may be similar to the inhibition by caffeine of L-type VGCCs in thalamocortical relay neurons [54]. Rankovic et al [54] suggested that, as in cardiac myocytes, the coupling between L-type VGCCs and RyRs in thalamocortical neurons occurs in a confined area where a cluster of RyRs is juxtaposed with a group of L-type VGCCs, forming a ‘Ca 2+ release unit’. They further suggested that the interaction between Ca 2+ release units is enhanced by caffeine, which increases the sensitivity of RyRs for Ca 2+ and evokes the spread of Ca 2+ -induced Ca 2+ release across the ER (possibly filling up a shell of Ca 2+ ions beneath the plasma membrane and allowing Ca 2+ cooperativity), or by neurotransmitter-stimulated recruitment of L-type VGCCs and RyRs.…”