Selective interference with TRPC3/6 channels disrupts OX1 receptor signalling via NCX and reveals a distinct calcium influx pathway.
TRPC channels play significant roles in the regulation of neuronal plasticity and development. The mechanism by which these nonselective cation channels exert their trophic actions appears to involve entry of Ca(2+) into the cells. Using a neuronal cell model (differentiated human IMR32 neuroblastoma cells), we demonstrate a central role for sodium entry via TRPC3/6 channels in receptor-mediated increases in intracellular calcium. These Na(+)-dependent Ca(2+) influxes, which were observed in a subpopulation of cells, were efficiently blocked by protein kinase C activation, by the Na(+)/Ca(2+) exchanger inhibitors, and by molecular disruption of TRPC3/6 channel function. On the other hand, another subpopulation of cells showed a Na(+)-independent Ca(2+) entry upon stimulation of the same receptors, orexin/hypocretin and bradykinin receptors. This second type of response was not affected by the above mentioned treatments, but it was sensitive to polyvalent cations, such as ruthenium red, spermine and Gd(3+). The data suggest that a NCX-TRPC channel interaction constitutes an important functional unit in receptor-mediated Ca(2+) influx in neuronal cells.
Louhivuori
Lauri M
LM
Biomedicum Helsinki, Institute of Biomedicine/Physiology, University of Helsinki, Finland.
Jansson
Linda
L
Nordström
Tommy
T
Bart
Geneviève
G
Näsman
Johnny
J
Akerman
Karl E O
KE
D002118:Calcium / Q000378:metabolism / Q000502:physiology*; D020013:Calcium Signaling / Q000502:physiology*; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D045744:Cell Line, Tumor; D018398:Homeodomain Proteins / Q000502:physiology*; D006801:Humans; D009447:Neuroblastoma / Q000737:chemistry / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D064446:Orexin Receptors; D011493:Protein Kinase C / Q000502:physiology; D018002:Receptors, Bradykinin / Q000502:physiology; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000502:physiology*; D018013:Receptors, Neuropeptide / Q000235:genetics / Q000502:physiology*; D012430:Ruthenium Red / Q000494:pharmacology; D019831:Sodium-Calcium Exchanger / Q000235:genetics / Q000502:physiology; D013096:Spermine / Q000502:physiology; D050052:TRPC Cation Channels / Q000037:antagonists & inhibitors / Q000502:physiology*; D000074287:TRPC6 Cation Channel
D018398:Homeodomain Proteins; D064446:Orexin Receptors; D018002:Receptors, Bradykinin; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide; D019831:Sodium-Calcium Exchanger; C491534:TLX2 protein, human; D050052:TRPC Cation Channels; C104603:TRPC3 cation channel; D000074287:TRPC6 Cation Channel; C117032:TRPC6 protein, human; D012430:Ruthenium Red; D013096:Spermine; D011493:Protein Kinase C; D002118:Calcium