Calcium binding proteins (CaBPs) are intracellular Ca2+ sensors that bind to Ca2+ and form a Ca2++CabP complex, which facilitate the activation of several enzymes and proteins and play a significant role in neurotransmission and the regulation of transcription factors (26). Among the numerous CaBPs, within the dopaminergic neurons of the midbrain, Calbindin D28K (CB), Calretinin (CR), and Parvalbumin (PV) are the most abundant (27).
A significant number of CB-immunoreactive neurons have been noted in both VTA and SNpc neurons. CB-positive neurons immunostain for TH, suggesting that the CB-immunoreactive neurons in the VTA and SNpc are dopaminergic. The CB-positive neurons are located mostly in the dorsal tier of the SNpc. The TH-positive neurons of the ventral tier of the SNpc lack CB-immunoreactivity (27-31).
CR is closely related to CB and has significant similarities in the homology of the amino acid sequence (32,33). CR-immunoreactive neurons are much less frequently observed in the entire brain. Approximately 50% of CR-immunoreactive cells in the SN/VTA complex also display TH-immunoreactivity (34,35). Within the midbrain, CR-immunoreactive cell bodies are more numerous in all the subdivisions of dopamine neurons of the VTA than in the SNpc. Within the SNpc, the CR-positive cells are more abundant in the dorsal tier of the SNpc than substantia nigra pars reticulate (SNpr) or substantia nigra pars lateralis (SNpl).
The distribution pattern of PV-immunoreactive neurons in the ventral mid-brain is distinctly different from the pattern of CB- and CR-immunoreactive neurons. PV-immunoreactive neurons are prominently absent in the dopaminergic neurons of the VTA and SNpc, but are expressed specifically in the gamma amino butyric acid (GABA)ergic nigrothalamic and nigrotectal neurons of the SNpr. The PV-positive neurons in the SNpr degenerate in progressive supranuclear palsy, but not in animal models of PD or idiopathic PD.
Administration of 6-hydroxydopamine (6-OHDA) and MPTP results in degeneration of the CB-negative TH-positive neurons in the SNpc, but not the TH- and CB-positive neurons in the dorsal tier of the SNpc (36,37). Similar to these animal models, in human PD, the CB- and CR-positive neurons in the dorsal tier of the SNpc are preserved, whereas the CB- and CR-negative ventral tier neurons of the SNpc degenerate significantly (37-39).
Although these studies in animals and humans suggest that the ventral tier of the SNpc dopamine neurons are more vulnerable to degeneration because of a lack of expression in CB, and that the VTA neurons are preserved because CB is coex-pressed with TH in these neurons, the precise mechanisms of action of CaBPs in their presumed neuroprotective role have not been established. Studies in CB null mutant mice, CB null mutant weaver mice (40), as well as in anoxic models of neuronal loss in the hippocampus (41) suggest that CB may not be required for neuroprotection.
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