Upregulation of D₂-class signaling in dopamine-denervated striatum is in part mediated by D₃receptors acting on Ca_V2.1 channels via PIP₂depletion

Abstract

The loss of dopaminergic neurons in the substantia nigra compacta followed by striatal dopamine depletion is a hallmark of Parkinson's disease. After dopamine depletion, dopaminergic D 2 receptor (D 2 R)-class supersensitivity develops in striatal neurons. The supersensitivity results in an enhanced modulation of Ca 2ϩ currents by D 2 R-class receptors. However, the relative contribution of D 2 R, D 3 R, and D 4 R types to the supersensitivity, as well as the mechanisms involved, have not been elucidated. In this study, whole cell voltage-clamp recordings were performed to study Ca 2ϩ current modulation in acutely dissociated striatal neurons obtained from rodents with unilateral 6-hydroxydopamine lesions in the substantia nigra compacta. Selective antagonists for D 2 R, D 3 R, and D 4 R types were used to identify whether the modulation by one of these receptors experiences a selective change after dopaminergic denervation. It was found that D 3 R-mediated modulation was particularly enhanced. Increased modulation targeted Ca V 2.1 (P/Q) Ca 2ϩ channels via the depletion of phosphatidylinositol 4,5-bisphosphate, an intracellular signaling cascade hard to detect in control neurons and hypothesized as being amplified by dopamine depletion. An imbalance in the striatal expression of D 3 R and its splice variant, D 3 nf, accompanied enhanced D 3 R activity. Because Ca V 2.1 Ca 2ϩ channels mediate synaptic GABA release from the terminals of striatal neurons, reinforcement of their inhibition by D 3 R may explain in part the profound decrease in synaptic strength in the connections among striatal projection neurons observed in the dopamine-depleted striatum.

Regulation of dopamine D3 receptor in the striatal regions and substantia nigra in diffuse Lewy body disease

“…BDNF from dopamine neurons is responsible for inducing normal expression of the dopamine D 3 receptor both during development and in adulthood. Recently an electrophysiological study showed that D 2 like receptors supersensitivity following DA depletion can in part be attributed to an enhanced D 3 receptor activity in striatal neurons (Prieto et al, 2011). Take together, all this data indicate that the reduction of D 3 receptor in PD may be attributed to the dopaminergic neuronal loss and a compensatory upregulation of the D 3 receptor in post synaptic neurons might be involved in the D 3 receptor regulation in PD or nonhuman PD models.…”

The neurobiology of impulse control disorders in Parkinson’s disease: from neurotransmitters to neural networks

“…Whether this is due to supplementing dopamine to a relatively spared ventral striatum, i.e., ‘overdose theory’ (Cools 2006; Voon et al 2011b) or dopamine denervation-induced receptor supersensitivity of D3 receptors in the ventral striatum (Prieto et al 2011; Vriend et al 2014b) is still unknown (Fig. 1).…”

Dopamine Receptors and Neurodegeneration

“…Furthermore the LID develops gradually over time and D2Rs, despite dopamine denervation increases the mRNA levels and protein, D2Rs are not further elevated in LID neither in animal models nor postmortem studies, as a matter of fact in PD patients L-DOPA normalizes the upregulation [157,158]. By then it was unclear whether or not the D3Rs subtype was participating in the supersentitivity by dopamine denervation, however their low expression in striatum made focus the attention in D2Rs [159,160]. In the last decade, D3Rs attracted the attention, it's important to mention that the helical transmembrane spanning region (TMS) of D2Rs and D3R receptors share 75-80% homology in amino-acid sequence and the TMS is directly involved in the orthosteric-binding site, main reason why targeting D3R has been challenging, however D3Rs-preferring compounds have been developed making possible the study of the role of D3Rs in PD.…”