A 5-HT(7) receptor-mediated depolarization in the anterodorsal thalamus. II. Involvement of the hyperpolarization-activated current I(h).
Previous studies have shown that 5-hydroxytryptamine (5-HT) can modulate the hyperpolarization-activated nonselective cation current (I(h)) to elicit a membrane depolarization in neurons. However, the receptor subtype involved in this response remains controversial. In the accompanying study, we have identified a 5-HT7 receptor-mediated depolarization in the anterodorsal nucleus of the thalamus (ADn). In the present study, we have examined the possible role of I(h) in mediating this 5-HT7 receptor-mediated depolarization. We used the blind tight-seal patch clamp technique to examine the ability of 5-HT to modulate I(h) in the ADn. We found that 5-HT induced a shift in the voltage dependence of I(h) to more depolarized potentials. The pharmacology of the receptor mediating this effect was consistent with that of a 5-HT7 receptor. Since the 5-HT7 receptor is coupled positively to adenylate cyclase, we examined the cAMP dependence of the 5-HT-induced modulation of I(h). Intracellular addition of cAMP mimicked and occluded the 5-HT response. Conversely, in the presence of the protein kinase inhibitors H-8 and staurosporine, ADn neurons still expressed a 5-HT-induced shift in the voltage dependence of I(h). These results suggest that 5-HT regulates I(h) in the ADn through a cAMP-dependent but protein kinase A (PKA)-independent mechanism. To determine the contribution of I(h) to the 5-HT7 receptor-mediated depolarization, we used the selective I(h) blocker ZD7288. This compound greatly reduced the depolarizing response elicited by activation of 5-HT7 receptors. We conclude that 5-HT7 receptors depolarize ADn neurons primarily by increasing I(h) through a cAMP-dependent, PKA-independent mechanism.
Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, MI 48201, USA.
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Chapin
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Andrade
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D000818:Animals; D000242:Cyclic AMP / Q000502:physiology; D066298:In Vitro Techniques; D007473:Ion Channels / Q000187:drug effects / Q000502:physiology*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000502:physiology*; D012701:Serotonin / Q000494:pharmacology; D015398:Signal Transduction; D013788:Thalamus / Q000187:drug effects / Q000502:physiology*
D007473:Ion Channels; D011985:Receptors, Serotonin; C104425:serotonin 7 receptor; D012701:Serotonin; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D000242:Cyclic AMP