title: Dual depolarization responses generated within the same  lateral septal neurons by TRPC4-containing channels.
abstract: In the central nervous system, canonical transient receptor potential (TRPC) channels have been implicated in mediating neuronal excitation induced by stimulating metabotropic receptors, including group 1 metabotropic glutamate receptors (mGluRs). Lateral septal (LS) neurons express high levels of TRPC4 and group I mGluRs. However, to what extent native TRPC4-containing channels (TRPC4-cc) are activated as well as the impact of different levels of TRPC4-cc activation on neuronal excitability remain elusive. Here, we report that stimulating LS neurons with group I mGluR agonist, (S)-3,5-DHPG, causes either an immediate increase in firing rate or an initial burst followed by a pause of firing, which can be correlated with below-threshold-depolarization (BTD) or above-threshold-plateau-depolarization (ATPD), respectively, in whole-cell recordings. The early phase of BTD and the entire ATPD are completely absent in neurons from TRPC4−/− mice. Moreover, in the same LS neurons, BTD can be converted to ATPD at more depolarized potentials or with a brief current injection, suggesting that BTD and ATPD may represent partial and full activations of TRPC4-cc, respectively. We show that coincident mGluR stimulation and depolarization is required to evoke strong TRPC4-cc current, and Na+ and Ca2+ influx, together with dynamic changes of intracellular Ca(2+), are essential for ATPD induction. Our results suggest that TRPC4-cc integrates metabotropic receptor stimulation with intracellular Ca(2+) signals to generate two interconvertible depolarization responses to affect excitability of LS neurons in distinct fashions.
authors.forename: Jinbin
authors.initials: J
authors.lastname: Tian
authors.forename: Dhananjay P
authors.initials: DP
authors.lastname: Thakur
authors.forename: Yungang
authors.initials: Y
authors.lastname: Lu
authors.forename: Yingmin
authors.initials: Y
authors.lastname: Zhu
authors.forename: Marc
authors.initials: M
authors.lastname: Freichel
authors.forename: Veit
authors.initials: V
authors.lastname: Flockerzi
authors.forename: Michael X
authors.initials: MX
authors.lastname: Zhu
mesh_terms: D000200:Action Potentials; D000818:Animals; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D064529:Receptor, Metabotropic Glutamate 5 / Q000378:metabolism; D012118:Resorcinols / Q000494:pharmacology; D012686:Septal Nuclei / Q000166:cytology / Q000378:metabolism*; D012964:Sodium / Q000378:metabolism; D050052:TRPC Cation Channels / Q000235:genetics / Q000378:metabolism*
chemical_list: D018690:Excitatory Amino Acid Agonists; D064529:Receptor, Metabotropic Glutamate 5; D012118:Resorcinols; D050052:TRPC Cation Channels; C489571:TRPC4 ion channel; C079215:3,5-dihydroxyphenylglycine; D012964:Sodium; D002118:Calcium; D005998:Glycine