Dopaminergic modulation of cultured rat olfactory receptor neurons

• Main Author: Vargas Granell, Gricelly
• Format: Dissertation
• Language: English
• Published: ProQuest Dissertations & Theses 01-01-1999
• Subjects: Neurology; Neurosciences; Pharmacology
• ISBN: 9780599492974; 059949297X

The presence of dopamine D2 receptors in olfactory receptor neurons (ORNs) suggests that odor sensitivity may be modulated by neurotransmitters at the level of primary sensory neurons. Because the hyperpolarization-activated, Ih, channel is present in ORNs, controls cell excitability and is modulated by dopamine in other systems, I used standard patch-clamp techniques to study the effects of dopamine on Ih in cultured rat ORNs. Application of 1 μM dopamine reversibly shifted Ih activation to more negative potentials and decreased Ih, maximal relative conductance. Sulpiride, a dopamine D2 receptor antagonist, blocked the effects of dopamine; while, quinpirole (selective D2 agonist) mimicked them. External application of an adenylyl cyclase inhibitor (SQ 22536) produced a reversible decrease in Ih peak currents, but had no effect OR Ih voltage dependence of activation. However, internal application of cAMP shifted Ih activation to more depolarized potentials. These findings showed that dopamine regulates Ih by activation of D2 receptors and subsequent inhibition of adenylyl cyclase. Whether this modulation resulted from a direct interaction of cAMP with the channel or a phosphorylation-dependent mechanism was unclear. I found that both cAMP (through a direct interaction with the channel) and PKA-mediated phosphorylation regulated the voltage dependence of Ih activation. In addition, PKA modulated Ih maximal relative conductance; cAMP had no effect. These results showed that, in rat ORNs, the voltage dependence of Ih activation is dually regulated by a direct action of cAMP on the channel and by PKA; while, the maximal conductance is regulated by phosphorylation alone. Since Ih contributes to the modulation of cell excitability, these findings suggest a mechanism by which dopaminergic reduction of cAMP levels and the phosphorylation state in ORNs would inhibit Ih and thereby alter resting properties as well as modulate odor sensitivity.