In Vivo Regulation of Homer1a Expression in the Striatum by Cocaine

Abstract

The glutamate receptor adaptor protein Homer is concentrated in the postsynaptic density of excitatory synapses and is critical for normal operation of synaptic transmission. In this study, we investigated the responsiveness of Homer family proteins to dopamine stimulation with the psychostimulant cocaine in rat striatal neurons both in vivo and in vitro. We found that a single dose of cocaine specifically induced a rapid and transient increase in protein levels of the Homer1a, but not Homer1b/c and Homer2a/b, isoforms in the striatum. This selective Homer1a induction was mediated primarily through activation of dopamine D1, but not D2, receptors. Both protein kinase A and Ca 2ϩ /calmodulin-dependent protein kinases are important for mediating the cocaine stimulation of Homer1a expression. At the transcriptional level, cAMP response element-binding protein serves as a prime transcription factor transmitting the signals derived from D1 receptors and associative pathways to the CaCRE sites within the Homer1a promoter. From a functional perspective, non-cross-linking Homer1a, once induced, competed with the cross-linking isoforms of Homer proteins (Homer1b/c and Homer2a/b) to uncouple the connection of group I metabotropic glutamate receptors (mGluRs) with inositol-1,4,5-triphosphate receptors. These results indicate that cocaine possesses the ability to stimulate Homer1a expression in striatal neurons through a specific synapse-to-nucleus pathway. Moreover, inducible Homer1a expression may represent a transcription-dependent mechanism underlying the dynamic regulation of submembranous macromolecular complex formation between group I mGluRs and their anchoring proteins.Synaptic Homer proteins are important for synaptic construction and function Sheng and Kim, 2002). Long-form Homer proteins (Homer1b/c, Homer2a/b, and Homer3) contain the N-terminal EVH1 (Enabled/ VASP homology 1) domain, which binds the C terminus of group I metabotropic glutamate receptors (mGluRs), whereas the C-terminal coiled-coil structure and leucine zipper motifs render a capability for self-assembly (Brakeman et al., 1997;Xiao et al., 1998;Xiao et al., 2000). Thus, as a prominent scaffolding molecule concentrated in the postsynaptic density of excitatory synapses, Homer crosslinks group I mGluRs to other targets in a specific subcellular microdomain to regulate a specific signaling activity. Emerging evidence indicates that Homer proteins play an essential role in the membrane trafficking of mGluR1␣/5 (Ango et al., 2000); the coupling of mGluR1/5 to inositol-1,4,5-triphosphate (IP 3 ) receptors and the cation (Ca 2ϩ or K ϩ ) channel (Yuan et al., 2003); the development of spines, axons, and synapses (Shiraishi et al., 2003); and drug addiction (Swanson et al., 2001;Szumlinski et al., 2004Szumlinski et al., , 2005; also see below).One distinctive member of Homer family is Homer1a (Brakeman et al., 1997;Xiao et al., 1998Xiao et al., , 2000. Unlike the long-form of Homer proteins, this short-form of Homer lacks the C-terminal coiled-co...

Homers regulate drug-induced neuroplasticity: Implications for addiction

“…Similarly, Ania-3 mRNA is up-regulated within frontal cortex by morphine in dependent animals, and this effect is observed also following naloxone-precipitated withdrawal [165]. A recent report by Zhang and colleagues [166] extended earlier data for cocaine-induced changes in Homer1a mRNA by demonstrating a transient (2-12 hrs), dose-dependent increase in Homer1a protein within both the dorsal and ventral aspects of the striatum following acute drug administration (see Table 2). Consistent with these data, immunoblotting studies in our laboratory have failed to detect changes in Homer1a levels within the PFC, NAC, dorsal striatum or hippocampus of either rats or mice at 3 weeks withdrawal from repeated cocaine injections (Table 2) [228].…”

“…As presented in Table 1, the mRNA for IEG Homer1 isoforms is up-regulated within 1-3 hours in brain following an acute cocaine injection [102,160,166]. In dorsal striatum, nucleus accumbens and frontal cortex, the elevation in Homer1a protein expression by an acute injection of cocaine resembles that of the IEG C-Fos, is dose-dependent and correlates with the magnitude of locomotor hyperactivity exhibited by rats [166].…”

“…Thus, while many drugs of abuse increase corticoaccumbens IEG Homer expression, this drug effect is transient and independent of a particular mechanism of drug action. In contrast to IEG Homers, the regulation of corticoaccumbens CC-Homer expression by drugs of abuse is more complex (Table 2) [39, 157,[166][167][168][169][170] and, as will be discussed below in greater detail, may reflect a compensatory response to either the immediate or longer-term effects of drug administration upon corticoaccumbens glutamate transmission.…”

“…In dorsal striatum, nucleus accumbens and frontal cortex, the elevation in Homer1a protein expression by an acute injection of cocaine resembles that of the IEG C-Fos, is dose-dependent and correlates with the magnitude of locomotor hyperactivity exhibited by rats [166]. By inhibiting plasma membrane transporters, cocaine prevents the re-uptake of dopamine, serotonin and norepinephrine and thus, enhances levels of these neurotransmitters within the synapse [228].…”

“…By inhibiting plasma membrane transporters, cocaine prevents the re-uptake of dopamine, serotonin and norepinephrine and thus, enhances levels of these neurotransmitters within the synapse [228]. Pretreatment of animals with the selective D1 receptor antagonist SCH23390, but not the selective D2 receptor antagonist eticlopride, prevents the cocaine-induced rise in striatal Homer1a protein expression supporting a key role for D1 receptor signaling in mediating this effect [166]. Moreover, in striatal cultures, a dopamine-induced induction in Homer1a expression could be mimicked by the protein kinase A (PKA) activator 8-bromo-cAMP and attenuated by the PKA inhibitor H89, the calcium/calmodulin-dependent protein kinase (CaMK) inhibitor KN62 or anti-sense oligonucleotides against the transcriptional regulator CREB (cAMP response element binding protein) [166].…”