Limits...
Hypocretin/Orexin neuropeptides: participation in the control of sleep-wakefulness cycle and energy homeostasis.

Nuñez A, Rodrigo-Angulo ML, Andrés ID, Garzón M - Curr Neuropharmacol (2009)

Bottom Line: These hypothalamic neurons are the origin of an extensive and divergent projection system innervating numerous structures of the central nervous system.In this respect, Hcrt/Orx activate two subtypes of G protein-coupled receptors (Hcrt/Orx1R and Hcrt/Orx2R) that show a partly segregated and prominent distribution in neural structures involved in sleep-wakefulness regulation.Wakefulness-enhancing and/or sleep-suppressing actions of Hcrt/Orx have been reported in specific areas of the brainstem.

View Article: PubMed Central - PubMed

Affiliation: Departamento de Anatomía, Histología y Neurociencia, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain. angel.nunez@uam.es

ABSTRACT
Hypocretins or orexins (Hcrt/Orx) are hypothalamic neuropeptides that are synthesized by neurons located mainly in the perifornical area of the posterolateral hypothalamus. These hypothalamic neurons are the origin of an extensive and divergent projection system innervating numerous structures of the central nervous system. In recent years it has become clear that these neuropeptides are involved in the regulation of many organic functions, such as feeding, thermoregulation and neuroendocrine and cardiovascular control, as well as in the control of the sleep-wakefulness cycle. In this respect, Hcrt/Orx activate two subtypes of G protein-coupled receptors (Hcrt/Orx1R and Hcrt/Orx2R) that show a partly segregated and prominent distribution in neural structures involved in sleep-wakefulness regulation. Wakefulness-enhancing and/or sleep-suppressing actions of Hcrt/Orx have been reported in specific areas of the brainstem. Moreover, presently there are animal models of human narcolepsy consisting in modifications of Hcrt/Orx receptors or absence of these peptides. This strongly suggests that narcolepsy is the direct consequence of a hypofunction of the Hcrt/Orx system, which is most likely due to Hcrt/Orx neurons degeneration.The main focus of this review is to update and illustrate the available data on the actions of Hcrt/Orx neuropeptides with special interest in their participation in the control of the sleep-wakefulness cycle and the regulation of energy homeostasis. Current pharmacological treatment of narcolepsy is also discussed.

No MeSH data available.


Related in: MedlinePlus

Schematic depiction of hypocretin/orexin system. Hypocretin-1/Orexin A (Hcrt-1/OrxA) and hypocretin-2/Orexin B (Hcrt-2/OrxB) are derived from a common precursor peptide, pre-pro-hypocretin. After removal of the N-terminal secretory signal sequence, pre-prohypocretin is cleaved at specific sites having basic amino acid residues to yield the two mature peptides. Hcrt-1/OrxA possesses two disulfide bridges while Hcrt-2/OxB is linear. The actions of hypocretins are mediated through interaction with two heterotrimeric G protein-coupled receptors (Hcrt/Orx1R and Hcrt/Orx2R), whose distribution in the central nervous system is regionally specific. Hcrt/Orx1R is more selective for Hcrt-1/OrxA, while Hcrt/Orx2R is equally specific for both peptides. Hcrt-1/OrxA is linked exclusively to excitatory G proteins of the Gq subclass, whereas Hcrt-2/OxB couples in vitro to excitatory Gq and/or inhibitory Gi/o. Signaling through Gq pathway results in increase of intracellular Ca2+, most probably via activation of phospholipase C-b with subsequent triggering of the phosphatidylinositol cascade and activation of protein kinase C. The Ca2+ influx likely induces depolarization. Signaling via inhibitory Gi/o pathway may occur through hyperpolarization due to K+ efflux (GIRK channel-mediated). Figure modified from [9].
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC2724663&req=5

Figure 1: Schematic depiction of hypocretin/orexin system. Hypocretin-1/Orexin A (Hcrt-1/OrxA) and hypocretin-2/Orexin B (Hcrt-2/OrxB) are derived from a common precursor peptide, pre-pro-hypocretin. After removal of the N-terminal secretory signal sequence, pre-prohypocretin is cleaved at specific sites having basic amino acid residues to yield the two mature peptides. Hcrt-1/OrxA possesses two disulfide bridges while Hcrt-2/OxB is linear. The actions of hypocretins are mediated through interaction with two heterotrimeric G protein-coupled receptors (Hcrt/Orx1R and Hcrt/Orx2R), whose distribution in the central nervous system is regionally specific. Hcrt/Orx1R is more selective for Hcrt-1/OrxA, while Hcrt/Orx2R is equally specific for both peptides. Hcrt-1/OrxA is linked exclusively to excitatory G proteins of the Gq subclass, whereas Hcrt-2/OxB couples in vitro to excitatory Gq and/or inhibitory Gi/o. Signaling through Gq pathway results in increase of intracellular Ca2+, most probably via activation of phospholipase C-b with subsequent triggering of the phosphatidylinositol cascade and activation of protein kinase C. The Ca2+ influx likely induces depolarization. Signaling via inhibitory Gi/o pathway may occur through hyperpolarization due to K+ efflux (GIRK channel-mediated). Figure modified from [9].

Mentions: Two independent research groups (the De Lecea and Sakurai groups) simultaneously described the existence of two peptides synthesized by hypothalamic neurons [18,75]. De Lecea and collaborators observed that these peptides are expressed by neurons in the posterolateral hypothalamus that are very similar to the secretin-related peptides, so they named them hypocretin-1 and hypocretin-2 (Hcrt-1 and Hcrt-2; [18]). At the same time, Sakurai et al. [74,75] reported that central administration of these peptides increased feeding behavior and called them orexin A (OrxA) and orexin B (OrxB). Hcrt/Orx neuropeptides act on two types of receptors (ORX1R and ORX2R; also known as Hcrtr1R and Hcrtr2R; [75]), which are expressed throughout the CNS (Fig. 1).


Hypocretin/Orexin neuropeptides: participation in the control of sleep-wakefulness cycle and energy homeostasis.

Nuñez A, Rodrigo-Angulo ML, Andrés ID, Garzón M - Curr Neuropharmacol (2009)

Schematic depiction of hypocretin/orexin system. Hypocretin-1/Orexin A (Hcrt-1/OrxA) and hypocretin-2/Orexin B (Hcrt-2/OrxB) are derived from a common precursor peptide, pre-pro-hypocretin. After removal of the N-terminal secretory signal sequence, pre-prohypocretin is cleaved at specific sites having basic amino acid residues to yield the two mature peptides. Hcrt-1/OrxA possesses two disulfide bridges while Hcrt-2/OxB is linear. The actions of hypocretins are mediated through interaction with two heterotrimeric G protein-coupled receptors (Hcrt/Orx1R and Hcrt/Orx2R), whose distribution in the central nervous system is regionally specific. Hcrt/Orx1R is more selective for Hcrt-1/OrxA, while Hcrt/Orx2R is equally specific for both peptides. Hcrt-1/OrxA is linked exclusively to excitatory G proteins of the Gq subclass, whereas Hcrt-2/OxB couples in vitro to excitatory Gq and/or inhibitory Gi/o. Signaling through Gq pathway results in increase of intracellular Ca2+, most probably via activation of phospholipase C-b with subsequent triggering of the phosphatidylinositol cascade and activation of protein kinase C. The Ca2+ influx likely induces depolarization. Signaling via inhibitory Gi/o pathway may occur through hyperpolarization due to K+ efflux (GIRK channel-mediated). Figure modified from [9].
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2724663&req=5

Figure 1: Schematic depiction of hypocretin/orexin system. Hypocretin-1/Orexin A (Hcrt-1/OrxA) and hypocretin-2/Orexin B (Hcrt-2/OrxB) are derived from a common precursor peptide, pre-pro-hypocretin. After removal of the N-terminal secretory signal sequence, pre-prohypocretin is cleaved at specific sites having basic amino acid residues to yield the two mature peptides. Hcrt-1/OrxA possesses two disulfide bridges while Hcrt-2/OxB is linear. The actions of hypocretins are mediated through interaction with two heterotrimeric G protein-coupled receptors (Hcrt/Orx1R and Hcrt/Orx2R), whose distribution in the central nervous system is regionally specific. Hcrt/Orx1R is more selective for Hcrt-1/OrxA, while Hcrt/Orx2R is equally specific for both peptides. Hcrt-1/OrxA is linked exclusively to excitatory G proteins of the Gq subclass, whereas Hcrt-2/OxB couples in vitro to excitatory Gq and/or inhibitory Gi/o. Signaling through Gq pathway results in increase of intracellular Ca2+, most probably via activation of phospholipase C-b with subsequent triggering of the phosphatidylinositol cascade and activation of protein kinase C. The Ca2+ influx likely induces depolarization. Signaling via inhibitory Gi/o pathway may occur through hyperpolarization due to K+ efflux (GIRK channel-mediated). Figure modified from [9].
Mentions: Two independent research groups (the De Lecea and Sakurai groups) simultaneously described the existence of two peptides synthesized by hypothalamic neurons [18,75]. De Lecea and collaborators observed that these peptides are expressed by neurons in the posterolateral hypothalamus that are very similar to the secretin-related peptides, so they named them hypocretin-1 and hypocretin-2 (Hcrt-1 and Hcrt-2; [18]). At the same time, Sakurai et al. [74,75] reported that central administration of these peptides increased feeding behavior and called them orexin A (OrxA) and orexin B (OrxB). Hcrt/Orx neuropeptides act on two types of receptors (ORX1R and ORX2R; also known as Hcrtr1R and Hcrtr2R; [75]), which are expressed throughout the CNS (Fig. 1).

Bottom Line: These hypothalamic neurons are the origin of an extensive and divergent projection system innervating numerous structures of the central nervous system.In this respect, Hcrt/Orx activate two subtypes of G protein-coupled receptors (Hcrt/Orx1R and Hcrt/Orx2R) that show a partly segregated and prominent distribution in neural structures involved in sleep-wakefulness regulation.Wakefulness-enhancing and/or sleep-suppressing actions of Hcrt/Orx have been reported in specific areas of the brainstem.

View Article: PubMed Central - PubMed

Affiliation: Departamento de Anatomía, Histología y Neurociencia, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain. angel.nunez@uam.es

ABSTRACT
Hypocretins or orexins (Hcrt/Orx) are hypothalamic neuropeptides that are synthesized by neurons located mainly in the perifornical area of the posterolateral hypothalamus. These hypothalamic neurons are the origin of an extensive and divergent projection system innervating numerous structures of the central nervous system. In recent years it has become clear that these neuropeptides are involved in the regulation of many organic functions, such as feeding, thermoregulation and neuroendocrine and cardiovascular control, as well as in the control of the sleep-wakefulness cycle. In this respect, Hcrt/Orx activate two subtypes of G protein-coupled receptors (Hcrt/Orx1R and Hcrt/Orx2R) that show a partly segregated and prominent distribution in neural structures involved in sleep-wakefulness regulation. Wakefulness-enhancing and/or sleep-suppressing actions of Hcrt/Orx have been reported in specific areas of the brainstem. Moreover, presently there are animal models of human narcolepsy consisting in modifications of Hcrt/Orx receptors or absence of these peptides. This strongly suggests that narcolepsy is the direct consequence of a hypofunction of the Hcrt/Orx system, which is most likely due to Hcrt/Orx neurons degeneration.The main focus of this review is to update and illustrate the available data on the actions of Hcrt/Orx neuropeptides with special interest in their participation in the control of the sleep-wakefulness cycle and the regulation of energy homeostasis. Current pharmacological treatment of narcolepsy is also discussed.

No MeSH data available.


Related in: MedlinePlus