Palmitoylation is a reversible post-translational addition of a 16-carbon lipid chain involved in trafficking and compartmentalizing target proteins. It is important for many cellular functions, including signaling via membrane-localized estrogen receptors (ERs). Within the nervous system, palmitoylation of ERα is necessary for membrane surface localization and mediation of downstream signaling through the activation of metabotropic glutamate receptors (mGluRs). Substitution of the single palmitoylation site on ERα prevents its physical association with the integral membrane protein caveolin-1 (CAV1), required for the formation of the ER/mGluR signaling complex. Interestingly, siRNA knockdown of either of two palmitoyl acyltransferases, zinc finger DHHC type-containing 7 (DHHC7) or DHHC21, also eliminates this signaling mechanism. Because ERα has only one palmitoylation site, we hypothesized that one of these DHHCs palmitoylates CAV1. We investigated this possibility by using an acyl-biotin exchange assay in HEK293 cells in conjunction with DHHC overexpression and found that DHHC7 increases CAV1 palmitoylation. Substitution of the palmitoylation sites on CAV1 eliminated this effect but did not disrupt the ability of the DHHC enzyme to associate with CAV1. In contrast, siRNA-mediated knockdown of DHHC7 alone was not sufficient to decrease CAV1 palmitoylation but rather required simultaneous knockdown of DHHC21. These findings provide additional information about the overall influence of palmitoylation on the membrane-initiated estrogen signaling pathway and highlight the importance of considering the influence of palmitoylation on other CAV1-dependent processes.
Our social relationships determine our health and well-being. In rodent models, there is now strong support for the rewarding properties of aggressive or assertive behaviors to be critical for the expression and development of adaptive social relationships, buffering from stress and protecting from the development of psychiatric disorders such as depression. However, due to the false belief that aggression is not a part of the normal repertoire of social behaviors displayed by females, almost nothing is known about the neural mechanisms mediating the rewarding properties of aggression in half the population. In the following study, using Syrian hamsters as a well-validated and translational model of female aggression, we investigated the effects of aggressive experience on the expression of markers of postsynaptic structure (PSD-95, Caskin I) and excitatory synaptic transmission (GluA1, GluA2, GluA4, NR2A, NR2B, mGluR1a, and mGluR5) in the nucleus accumbens (NAc), caudate putamen and prefrontal cortex. Aggressive experience resulted in an increase in PSD-95, GluA1 and the dimer form of mGluR5 specifically in the NAc 24 h following aggressive experience. There was also an increase in the dimer form of mGluR1a 1 week following aggressive experience. Aggressive experience also resulted in an increase in the strength of the association between these postsynaptic proteins and glutamate receptors, supporting a common mechanism of action. In addition, 1 week following aggressive experience there was a positive correlation between the monomer of mGluR5 and multiple AMPAR and NMDAR subunits. In conclusion, we provide evidence that aggressive experience in females results in an increase in the expression of postsynaptic density, AMPARs and group I metabotropic glutamate receptors, and an increase in the strength of the association between postsynaptic proteins and glutamate receptors. This suggests that aggressive experience may result in an increase in excitatory synaptic transmission in the NAc, potentially encoding the rewarding and behavioral effects of aggressive interactions.
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