Signal Transduction Systems Of Orexin Receptors

Both OX1R and OX2R are G-protein coupled receptors, which transmit information into cells by activating heterotrimeric G proteins. Activation of the signaling pathways associated with distinct G-proteins may contribute to the diverse physiological roles of orexin in particular neurons. Although many G-protein-coupled neurotransmitter receptors are potentially capable of modulating both voltage-dependent calcium channels and G-protein-gated inwardly rectifier potassium channels (GIRKs), there might be a substantial degree of selectivity in the coupling to one or other of these channels in neurons (Fig. 3). The signal transduction pathways of orexin receptors were examined in cells transfected with OX1R or OX2R. In OX1R-expressing cells, forskolin-stimulated cAMP was not affected by orexin administration. In addition, PTX treatment did not show any effects on orexin-induced increases in [Ca2+] ยก. These results suggest that OX1R does not couple to PTX-sensitive G l/o proteins.12 In contrast, orexin inhibited forskolin-stimulated cAMP production in a dose-dependent manner in OX2R-expressing cells. The effect was abolished by pretreatment with PTX. However, orexin-induced increases in [Ca2+]i was not affected by PTX treatment in OX2R-expressing cells. These results indicate that the OX2R couples to PTX-sensitive G proteins which were involved in the inhibition of adenylyl cyclase by orexin. These results suggest that OX1R couples exclusively to PTX-insensitive G proteins, and OX2R couples to both PTX-sensitive and -insensitive proteins (Fig 3). The relative contribution of these G-proteins in the regulation of neuronal activity remains unknown. Orexins have been shown to have an excitatory activity in many types of neurons in vivo. For instance, noradrenergic cells of the LC,13 dopaminergic cells of the ventral tegmental area,14 and histaminergic cells from the TMN15 have been shown to be activated by orexins. Because, LC neurons exclusively express OX1R, while TMN neurons exclusively express OX2R, these observations suggest that both OX1R and OX2R signaling are basically excitatory on neurons.

However, these studies only examined effect of orexins on receptor-expressing cell bodies. There is a possibility that orexin receptors are also on presynaptic terminals, because Li et al. 16 reported that orexin increases local glutamate signalling by facilitation of glutamate release from presynaptic terminals. Therefore, it is possible that activation of PTX-sensitive G proteins in the downstream of OX2R might be involved in functions other than activation of neurons, such as in the tips of developing neurites and on presynaptic nerve terminals, leading to growth cone collapse and enhanced synaptic release of the transmitter. Alternatively, OX2R mediated activation of Gi might result in inhibition of some population of neurons. In fact, orexin was recently reported to inhibit proopio-melanocortin neurons in the arcuate nucleus in vitro.17

Orexin Signal Transduction Pathway
Figure 3. Schematic drawing of the intracellular signal transduction systems of orexin receptors in neurons. OX1R is coupled exclusively to the Gq subclass of heterotrimeric G proteins, whereas OX2R may couple to Gi/o, and/or Gq.

The other reports also suggested that in adrenocortical cells, orexins stimulate corticosterone secretion through the activation of the adenlylate cyclase-dependent signaling via an activation of OX2R.18-20 The induction of cAMP in the adrenal cortex might be a cell-type dependent phenomenon, since in PC12 cells, orexins inhibited the PACAP-induced increase in the cAMP.21 These differences in G-protein coupling might be influenced by receptor density and/or densities in each G-proteins.

Recently, several studies showed molecular interactions and cross-talks between orexin receptors and other receptors. Hilairet et al. showed that when the cannabinoid receptor (CB1) and OX1R are co-expressed, there is a CB1-dependent enhancement of the orexin A potency to activate the mitogen-activated protein kinase pathway. It was also shown that CB1 and OX1R are closely apposed at the plasma membrane to form

Table 1: Distribution of OX1R and OX2R in the rat brain. The relative density of labeling is classified as:

Region

Ox1

Ox1r

Ox2r

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  • thomas
    How does orexin signal?
    8 years ago

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