Copper: from neurotransmission to neuroproteostasis

Abstract

Copper is critical for the Central Nervous System (CNS) development and function. In particular, different studies have shown the effect of copper at brain synapses, where it inhibits Long Term Potentation (LTP) and receptor pharmacology. Paradoxically, according to recent studies copper is required for a normal LTP response. Copper is released at the synaptic cleft, where it blocks glutamate receptors, which explain its blocking effects on excitatory neurotransmission. Our results indicate that copper also enhances neurotransmission through the accumulation of PSD95 protein, which increase the levels of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors located at the plasma membrane of the post-synaptic density. Thus, our findings represent a novel mechanism for the action of copper, which may have implications for the neurophysiology and neuropathology of the CNS. These data indicate that synaptic configuration is sensitive to transient changes in transition metal homeostasis. Our results suggest that copper increases GluA1 subunit levels of the AMPA receptor through the anchorage of AMPA receptors to the plasma membrane as a result of PSD-95 accumulation. Here, we will review the role of copper on neurotransmission of CNS neurons. In addition, we will discuss the potential mechanisms by which copper could modulate neuronal proteostasis ("neuroproteostasis") in the CNS with focus in the Ubiquitin Proteasome System (UPS), which is particularly relevant to neurological disorders such as Alzheimer's disease (AD) where copper and protein dyshomeostasis may contribute to neurodegeneration. An understanding of these mechanisms may ultimately lead to the development of novel therapeutic approaches to control metal and synaptic alterations observed in AD patients.

Keywords: AMPA; E-ligases; copper; hippocampal neurons; neurotransmission; proteasome; synaptic activity; ubiquitination.

Figure 1

Copper modulates neurotransmission by a biphasic mechanism. The scheme depicts the effect of copper on neurotransmission in acute and chronic conditions. Copper acts as a channel blocker under acute conditions. Sustained release of copper from the presynaptic vesicles to the synaptic cleft will lead to an increase in intracellular copper at the postsynaptic neuron, where copper might regulate the levels of scaffolding proteins that modulate the localization of channels at the plasma membrane (Peters et al., 2011).

Figure 2

Proposed model of how copper enhances neurotransmission by acting on UPS. Ubiquitin (Ub) is sequentially transferred from E1-activating enzyme to E2-conjugating enzyme, and then transferred to PSD95 by the action of an E3-ligase, which lead to PSD95 degradation into the Proteasome. Under low copper levels (control), small number of AMPA receptors are located at the plasma membrane. Under chronic copper release, levels of PSD95 are increased leading to the clustering of AMPA receptors located at the plasma membrane. Copper may promote the ubiquitination of PSD95 by acting as a cofactor of the E1-E2-E3 enzymes, promoting the ubiquitination of PSD95 and a subsequent saturation of the proteasome, slowing down PSD95 degradation leading to AMPA receptor clustering at the plasma membrane. Alternatively, copper can inhibit the proteasome directly impeding PSD95 degradation and promoting the formation of AMPA clusters at the postsynaptic membrane with a concomitant enhancement of AMPAergic neurotransmission.