The Hypocretin System

Hypocretins (Hcrt-1 and Hcrt-2) are derived from a common pre-pro-hypocretin gene expressed in a small group of hypothalamic neurons located in the perifornical area. Hypocretin neurons have widespread projections,32,33 densely accumulating in infralimbic central representations of the sympathetic nervous system,9,12,34 and intero- and nociception.35-37 In their targets within38 and even outside the nervous system Hcrt-1 and Hcrt-2 both act on two G-Protein coupled receptors exhibiting differential agonist affinity and expression throughout and even outside the nervous system.38 They couple to

O. Selbach and H.L. Haas. Heinrich-Heine-University. Institute of Physiology D-40225 Dusseldorf pertussistoxin-sensitive and -insensitive, PLC-dependent, calcium-sensitive and calcium-insensitive signal transduction mechanisms, some of which exhibit rather unusual effector pathways25 (reviewed by Kukkonen and Akerman in this book). These include Hcrt2-receptor mediated activation of electrogenic sodium-calcium exchangers (NCX)14'15'18'39'40 or Hcrtl-receptor mediated activation of non-specific cationic conductances.9'20'25 Other signal transduction pathways include activation of L-type voltage-dependent calcium channels,25 closure of G-protein activated inward rectifier potassium channels (GIRK),41 and activation of plasticity-related kinases,30 including PKC, PKA,22'42 and MAPK,25 as well as release of mitochondrial pro-apoptotic factors.43

Single cell RT-PCR and whole cell patch clamp recordings of acutely isolated aminergic neurons revealed a striking coexpression of serotonin 5-HT2C receptors and NCX in TMN neurons,18 and a high but subunit- and cell-type specific coexpression of non-specific cationic conductances of the transient receptor potential channel family (TRPC) in all aminergic but not locus coeruleus neurons (Figure 1).19 TRPC, evolutionary conserved cellular sensors for a variety of stimuli,44 and NCX, set points for cellular calcium homeostasis and survival,45 thus link hypocretin and aminergic signaling.

2.1. Glutamate and GABA

Glutamate and gamma-aminobutyric acid (GABA) are the most abundant excitatory and inhibitory neurotransmitters in the nervous system.6,2635 Although hypothalamic hypocretin neurons in vitro may be in an intrinsic state of depolarization,28 their activity is also driven by a glutamatergic excitatory feed forward mechanism.26 In fact, hypocretin neurons exhibit glutamate immunoreactivity and express specific vesicular glutamate transporters, suggesting that they release glutamate by themselves.46 In turn, the activity of Hcrt neurons in vitro is limited by inhibitory constraints including tonic activation of presynaptic type III metabotropic glutamate autoreceptors (mGluR)47 and negative feedback through GABAergic,48 catecholaminergic, serotonergic, and purinergic signals activating postsynaptic metabotropic GABAb, catecholamine (a2), serotonin (5-HT1A), and adenosine (A1) receptors. Coupled to Gl/o-proteins these receptors all converge on inward rectifier potassium (GIRK) channels, which inhibit hypocretin neurons by hyperpolarization.2649 A major inhibitory GABA-galaninergic pathway to the posterior hypothalamus emanates from sleep-active neurons in the ventrolateral preoptic area (VLPO).50-52 Mutual inhibition between these neurons and the ascending aminergic systems has been proposed to form a bistable flip-flop sleep-switch gating rapid transitions between behavioral states61353 and other homeostatic body functions.35

A common feature of hypocretins apart from their predominant neuroexcitatory actions1 is that they increase impulse flow in GABAergic (inte^nem-ons16,39,40,54 and facilitate the release of glutamate in many if not all targets.263055-57 Whereas the excitatory direct effects of hypocretins on aminergic and GABAergic cells depend on activation of postsynaptic Hcrt-receptors,92025 modulation of glutamate, GAB A,163940 and amine30,56,58 release relies on presynaptic mechanisms, involving modulation of presynaptic calcium homeostasis and/or sensitization of parts of the release machinery such as Rab3, implicated in both behavioral state control and synaptic plasticity.59 Dissociated pre- and postsynaptic inhibitory and excitatory hypocretin effects promote network bistability660 and negative feedback protecting from excitotoxicity.43,45,61

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