Abstract
The precise regulation of synaptic integrity is critical for neuronal network connectivity and proper brain function. Essential aspects of the activity and localization of synaptic proteins are regulated by posttranslational modifications. S-palmitoylation is a reversible covalent modification of the cysteine with palmitate. It modulates affinity of the protein for cell membranes and membranous compartments. Intracellular palmitoylation dynamics are regulated by crosstalk with other posttranslational modifications, such as S-nitrosylation. S-nitrosylation is a covalent modification of cysteine thiol by nitric oxide and can modulate protein functions. Therefore, simultaneous identification of endogenous site-specific proteomes of both cysteine modifications under certain biological conditions offers new insights into the regulation of functional pathways. Still unclear, however, are the ways in which this crosstalk is affected in brain pathology, such as stress-related disorders. Using a newly developed mass spectrometry-based approach Palmitoylation And Nitrosylation Interplay Monitoring (PANIMoni), we analyzed the endogenous S-palmitoylation and S-nitrosylation of postsynaptic density proteins at the level of specific single cysteine in a mouse model of chronic stress. Among a total of 813 S-PALM and 620 S-NO cysteine sites that were characterized on 465 and 360 proteins, respectively, we sought to identify those that were differentially affected by stress. Our data show involvement of S-palmitoylation and S-nitrosylation crosstalk in the regulation of 122 proteins including receptors, scaffolding proteins, regulatory proteins and cytoskeletal components. Our results suggest that atypical crosstalk between the S-palmitoylation and S-nitrosylation interplay of proteins involved in synaptic transmission, protein localization and regulation of synaptic plasticity might be one of the main events associated with chronic stress disorder, leading to destabilization in synaptic networks.
Highlights
Synaptic plasticity is a dynamic process that is driven by molecular changes at individual synapses that lead to the rapid and recurrent rewiring of neuronal circuitry (Amtul and Atta-Ur-Rahman, 2015, Holtmaat and Svoboda, 2009)
Our results indicated that the mechanisms of crosstalk between the S-PALM and SNO of proteins that are involved in synaptic transmission, synaptic localization, and the regulation of synaptic plasticity might be a major event that is associated with chronic stressrelated disorders, leading to the rewiring of neuronal circuitry
To analyze the S-PALM of the synaptic proteome under physiological conditions, we used enriched fractions of PSD proteins that were obtained from brain synaptoneurosomes of control mice (Fig. S1A)
Summary
Synaptic plasticity is a dynamic process that is driven by molecular changes at individual synapses that lead to the rapid and recurrent rewiring of neuronal circuitry (Amtul and Atta-Ur-Rahman, 2015, Holtmaat and Svoboda, 2009). Synaptic proteins are regulated by a wide range of posttranslational modifications (PTMs), including S-palmitoylation (S-PALM) and S-nitrosylation (S-NO). These chemical modifications affect the properties of target molecules, resulting in the modulation of synaptic function and plasticity (Karve and Cheema, 2011, Okamoto et al, 2014, Yokoi et al, 2012). Ho et al recently provided evidence of reciprocal regulation of the major postsynaptic protein postsynaptic density protein 95 (PSD-95) by S-NO and S-PALM (Ho et al, 2011) They noted that the decrease in PSD-95 S-PALM increased its S-NO, suggesting that the specific sites of PSD-95 protein may undergo S-PALM or S-NO in a competitive manner. In turn, inhibited PSD-95 S-PALM and reduced the amount of this protein at the synapse
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