Figure 1.

The schematic diagram is a hypothetical depiction of the H₃ receptor-mediated signalling pathways in the CNS and their probable implications. Activation of H₃ receptor, constitutively or in presence of an agonist, leads to the activation of many G_i/o-associated intracellular pathways. Active G_i/o-proteins negatively couple AC, thereby inhibiting the cAMP/PKA cascade and subsequent lowering of cAMP responsive element binding protein (CREB), a pro-survival transcription factor. Reduction in PKA activity may decrease release of neurotransmitters, for example histamine (HA), GABA, etc. Additionally, H₃ receptor activation also activates PI3K and MAPK pathways. Activated PI3K then activates Akt, a serine threonine kinase, which phosphorylates and hence inactivates pro-apoptotic GSK-3β. In the MAPK pathway, especially p44 and p42 MAPK (ERK1/2) are coupled to H₃ receptors; activated ERK has also been linked to epilepsy. The other three pathways known so far that are modulated upon H₃ receptor activation include increased activity of the enzyme PLA₂, whose inhibition confers neuroprotection in epileptic models; mobilization of intracellular Ca²⁺[Ca²⁺]_i; and finally the inhibition of Na⁺/H⁺ exchanger (NHE), a protein that buffers intra-neuronal pH and it's defective functioning is also implicated in epilepsy. Also, H₃ receptors possibly influence the function of other GPCRs and vice versa (e.g. dopamine D₁ receptor) by virtue of cross talk in heteromer containing cells.