Modulation of Dopaminergic Neuronal Excitability by Zinc through the Regulation of Calcium-related Channels

Abstract

Depending on the intracellular buffering of calcium by chelation, zinc has the following two apparent effects on neuronal excitability: enhancement or reduction. Zinc increased tonic activity in the depolarized state when neurons were intracellularly dialyzed with EGTA but attenuated the neuronal activity when BAPTA was used as an intracellular calcium buffer. This suggests that neuronal excitability can be modulated by zinc, depending on the internal calcium buffering capacity. In this study, we elucidated the mechanisms of zinc-mediated alterations in neuronal excitability and determined the effect of calcium-related channels on zinc-mediated alterations in excitability. The zinc-induced augmentation of firing activity was mediated via the inhibition of small-conductance calcium-activated potassium (SK) channels with not only the contribution of voltage-gated L-type calcium channels (VGCCs) and ryanodine receptors (RyRs), but also through the activation of VGCCs via melastatin-like transient receptor potential channels. We suggest that zinc modulates the dopaminergic neuronal activity by regulating not only SK channels as calcium sensors, but also VGCCs or RyRs as calcium sources. Our results suggest that the cytosolic calcium-buffering capacity can tightly regulate zinc-induced neuronal firing patterns and that local calcium-signaling domains can determine the physiological and pathological state of synaptic activity in the dopaminergic system.

Characterization of two cDNAs encoding pH-sensitive and zinc-gated chloride channels in the fall armyworm, Spodoptera frugiperda

“…The zinc ions are concentrated into synaptic vesicles via the zinc transporter 7 37 , and are released to the synaptic cleft during neuronal excitation 38 . Synaptically released zinc ions modulated a variety of ionotropic receptors, including GABAR 39 , glycine receptors 40 , voltage-gated calcium channels 41 , transient receptor potential ankyrin 1 42 ,voltage-gated potassium channels and voltage-gated sodium channels 43 . Moreover, the ZAC, which is highly expressed in the human stomach, was found to be activated by zinc and H +17 .…”

General Aspects of Metal Ions as Signaling Agents in Health and Disease

“…In the membrane of postsynaptic neurons, zinc ions can cause a number of excitatory or inhibitory reactions by interacting with different receptors, and the best-known targets are N-methyl-D-aspartate glutamate receptor (NMDAR) [ 107 , 119 ], alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (APMAR) [ 120 , 121 ], or voltage-gated Ca 2+ channels [ 122 , 123 ]. The concentration of zinc ions in the postsynaptic nerve terminals is controlled by the ZnT-1 transporter activity; the expression of this transporter depends on the number of free zinc ions within the cell [ 124 ].…”