Kv4.2 mediates histamine modulation of preoptic neuron activity and body temperature.
Histamine regulates arousal, circadian rhythms, and thermoregulation. Activation of H3 histamine receptors expressed by preoptic GABAergic neurons results in a decrease of their firing rate and hyperthermia. Here we report that an increase in the A-type K⁺ current in preoptic GABAergic neurons in response to activation of H3 histamine receptors results in decreased firing rate and hyperthermia in mice. The Kv4.2 subunit is required for these actions in spite of the fact that Kv4.2⁻/⁻ preoptic GABAergic neurons display A-type currents and firing characteristics similar to those of wild-type neurons. This electrical remodeling is achieved by robust upregulation of the expression of the Kv4.1 subunit and of a delayed rectifier current. Dynamic clamp experiments indicate that enhancement of the A-type current by a similar amount to that induced by histamine is sufficient to mimic its robust effect on firing rates. These data indicate a central role played by the Kv4.2 subunit in histamine regulation of body temperature and its interaction with pERK1/2 downstream of the H3 receptor. We also reveal that this pathway provides a mechanism for selective modulation of body temperature at the beginning of the active phase of the circadian cycle.
The Department of Molecular and Integrative Neurosciences, The Scripps Research Institute, La Jolla, California, United States of America.
Jasmine
J
Sethi
Manuel
M
Sanchez-Alavez
Iustin V
IV
Tabarean
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001831:Body Temperature / Q000187:drug effects / Q000502:physiology*; D002940:Circadian Rhythm / Q000187:drug effects; D059330:GABAergic Neurons / Q000187:drug effects / Q000378:metabolism; D006632:Histamine / Q000378:metabolism*; D017442:Histamine Agonists / Q000494:pharmacology; D007267:Injections; D015640:Ion Channel Gating / Q000187:drug effects; D007700:Kinetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D009474:Neurons; D018408:Patch-Clamp Techniques; D011301:Preoptic Area / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D021122:Protein Subunits / Q000378:metabolism; D018100:Receptors, Histamine H3 / Q000378:metabolism; D051672:Shal Potassium Channels / Q000172:deficiency / Q000378:metabolism*; D013111:Spider Venoms / Q000008:administration & dosage / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects
D017442:Histamine Agonists; D021122:Protein Subunits; D018100:Receptors, Histamine H3; D051672:Shal Potassium Channels; D013111:Spider Venoms; C493513:phrixotoxin I, Phrixotrichus auratus; D006632:Histamine