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  • br Results br Discussion br Conclusions The

    2019-09-10


    Results
    Discussion
    Conclusions The present study demonstrates that CRF1 receptor-deficiency prolongs whereas CRF2 receptor-deficiency shortens the duration of recognition memory deficits induced by morphine discontinuation, unraveling opposite roles for the two known CRF receptor subtypes in cognitive dysfunction associated with opiate withdrawal. Moreover, either CRF1 or CRF2 receptor-deficiency abolishes the stress-induced reemergence of recognition memory deficits longtime after cessation of morphine administration, indicating that both CRF receptor subtypes mediate the long-lasting vulnerability induced by opiate withdrawal. Cognitive dysfunction and the long-lasting vulnerability to stressors are critical features of substance use disorders. In this framework, the present findings suggest that functional antagonism of the CRF system, especially of the CRF/CRF2 receptor pathway, might effectively attenuate cognitive dysfunction and the persistent vulnerability following opiate withdrawal, thus facilitating substance-abstinence in substance-withdrawn patients.
    Acknowledgments The authors wish to thank Anne Fayoux and Stéphane Lelgouach for valuable assistance with animal care. This study was supported by the Institut de Recherche Servier (IDRS), the Université de Bordeaux, the Centre National de la Recherche Scientifique (CNRS) and the Fondation pour la Recherche Médicale (FRM grant n. DPA20140629794).
    Introduction The cytokine receptors form a structural family that can be divided into two ifenprodil clinical based on conserved features in the extracellular domains (ECDs), particularly the number and spacing of cysteine and proline residues [1], [2]. This classification promoted investigations into the evolution, structure and function of the cytokine receptors, and has permitted useful generalizations about the members of the families, and judicious extrapolations from one cytokine/receptor pair to another. The CRF2 receptors are listed in Table 1A and B. The corresponding Class II cytokines are organized by families in Table 2, and are diagrammatically paired with their receptors in Fig. 1. All the receptors except TF appear to function as heterodimers (see below). Although this review will focus on the CRF2 family of receptors, it is worthwhile to introduce their ligands, which can be divided into several groups based on both structure and function (Table 2). Several structure/function reviews have appeared for the best studied cytokine receptors, particularly those with crystal structures [21], [22]. In addition, the genetics, evolution and structure of the chromosome 21-encoded CRF2 receptors, particularly IFNAR, have been summarized [23].
    The Class II cytokine receptors (CRF2) The CRF2 proteins are tripartite single-pass transmembrane proteins defined by structural similarities in the extracellular domain, which includes the ligand-binding residues [1], [2], [24]. The 200-amino-acid extracellular domain, more specifically denoted a cytokine receptor homology (CRH) domain, is composed of 2 tandem fibronectin Type III (FNIII) domains, a structural motif in the immunoglobulin fold superfamily (Fig. 2). We will refer to the amino-terminal FNIII domain, distal to the membrane, as D1, and the membrane-proximal domain as D2. Each FNIII domain has a structural framework of seven β-strands connected by loops, and organized into two apposed β-sheets (although there are variations of this structure, including the division of some β strands into two short strands, and the occurrence of short α- or 310-helices in loop regions). Within these domains is a pattern of hydrophobic and hydrophilic amino acids typical of β strands. In addition, the position of several conserved cysteines and a completely conserved tryptophan characterize the cytokine receptor family. The Class I and Class II receptors are distinguished by the positions of class-specific cysteine residues, and by the presence of a highly conserved pattern “WSXWS” in the carboxyl terminal half (D2 domain) of Class I receptors; in the Class II receptors, this sequence is substituted by various sequences which appear to preserve the three-dimensional fold of this segment.