Haloperidol and Clozapine Differentially Affect the Expression of Arrestins, Receptor Kinases, and Extracellular Signal-Regulated Kinase Activation

Abstract

Dopamine and other G protein-coupled receptors (GPCRs) represent the major target of antipsychotic drugs. GPCRs undergo desensitization via activation-dependent phosphorylation by G protein-coupled receptor kinases (GRKs) followed by arrestin binding. Arrestins and GRKs are major regulators of GPCR signaling. We elucidated changes in expression of two arrestins and four GRKs following chronic (21 days) treatment with haloperidol (1 mg/kg i.p.) or clozapine (20 mg/kg i.p.) 2 or 24 h after the last injection in 11 brain regions. Haloperidol decreased GRK3 in ventrolateral caudate-putamen and transiently down-regulated GRK5 in globus pallidus and caudal caudate-putamen. Clozapine also caused a short-term suppression of the GRK5 expression in the caudal caudate-putamen and globus pallidus, but, unlike haloperidol, elevated GRK5 in the caudal caudate-putamen after 24 h. Unlike haloperidol, clozapine decreased arrestin2 and GRK3 in hippocampus and GRK3 in globus pallidus but increased arrestin2 in the core of nucleus accumbens and ventrolateral caudate-putamen and GRK2 in prefrontal cortex. Clozapine, but not haloperidol, induced long-term activation of extracellular signalregulated kinase (ERK) 2 in ventrolateral caudate-putamen and transient in prefrontal cortex. The data demonstrate that haloperidol and clozapine differentially affect the expression of arrestins and GRKs and ERK activity, which may play a role in determining their clinical profile.

Abnormal Activity of the MAPK- and cAMP-Associated Signaling Pathways in Frontal Cortical Areas in Postmortem Brain in Schizophrenia

“…Indeed, animal studies have demonstrated that signaling molecules are targets of modification with antipsychotic treatment. Proteins downstream of cAMP-and MAPKassociated pathways are changed after acute and chronic antipsychotic treatment (Ahmed et al, 2008;Molteni et al, 2009). Additionally, the pharmacological activity of nicotine has been shown to act via these same signaling pathways (Mobascher and Winterer, 2008).…”

The Physiology, Signaling, and Pharmacology of Dopamine Receptors

“…GRK2 is widely expressed in the brain, including primary dopaminergic areas (Arriza et al, 1992) and can phosphorylate and regulate D1, D2, and D3 dopamine receptors in in vitro cellular systems (Tiberi et al, 1996;Iwata et al, 1999;Kim et al, 2001;Kabbani et al, 2002;Sedaghat et al, 2006;Banday et al, 2007). Indirect evidence for the role of this kinase in the regulation of dopamine receptors was provided by the observation of alterations in the GRK2 expression levels in the striatum of animals with experimental parkinsonism (Bezard et al, 2005), rats treated with antipsychotics (Ahmed et al, 2008b), and rats receiving long-term cocaine treatment (Schroeder et al, 2009). Whereas a deletion of the GRK2 gene in mice results in embryonic lethality, presumably as a result of cardiac hypoplasia , mice heterozygous for this mutation are viable and were used to investigate the role of GRK2 in dopamine receptor functioning .…”

Rich Tapestry of G Protein-Coupled Receptor Signaling and Regulatory Mechanisms

“…Evolution endowed mammals with ϳ1000 different GPCRs (Römpler et al, 2007) that are phosphorylated by seven GRKs (Moore et al, 2007) and a number of other kinases (Budd et al, 2000;Naik et al, 2005;Luo et al, 2008) and interact with four arrestin subtypes (Gurevich and Gurevich, 2006b). Each tissue and cell has a unique complement of receptors (Penn et al, 2001), GRKs and arrestins (Penn et al, 2001;Gurevich et al, 2002;Ahmed et al, 2008a,b;Bychkov et al, 2008) that changes, sometimes quite dramatically, during development (Gurevich et al, 2002, disease (Ahmed et al, 2008a;Bychkov et al, 2008), and drug treatment (Ahmed et al, 2008b). To make matters even more complicated, phosphorylation of the same receptor at different sites (Pals-Rylaarsdam et al, 1997; Lee et al, 2000;Key et al, 2003;Jones and Hinkle, 2008), by different GRKs Ren et al, 2005;Luo et al, 2008), or even by the same GRK to different levels (Vishnivetskiy et al, 2007) generates functionally distinct receptor species that bind arrestins with different biological consequences.…”