Identification of a Long-Lasting Form of Odor Adaptation that Depends on the Carbon Monoxide/cGMP SecondMessenger System

Abstract

The diffusible messenger carbon monoxide (CO) has been proposed to mediate endogenous cyclic guanosine 3Ј,5Ј-monophosphate (cGMP) formation and sensory adaptation in vertebrate olfactory receptor neurons (ORNs). We have identified and characterized a long-lasting form of odor response adaptation (LLA) that operates at the level of isolated salamander ORNs and does not require any interactions from other cells. Manifestations of LLA are seen in reduced amplitude and prolonged kinetics of the cAMP-mediated excitatory odor response and the generation of a persistent current component that lasts for several minutes and is attributable to cyclic nucleotide-gated (CNG) channel activation by cGMP. Because these effects can be mimicked by micromolar amounts of exogenous cGMP or CO, we applied various inhibitors of cGMP formation. LLA is abolished selectively by heme oxygenase inhibitors known to prevent CO release and cGMP formation in ORNs, whereas odor excitation remains unaffected. In contrast, blockers of nitric oxide synthase are unable to eliminate LLA. Several controls rule out a contribution of nonspecific actions to the effects of CO inhibitors. The results indicate that endogenous CO/cGMP signals contribute to olfactory adaptation and underlie the control of gain and sensitivity of odor transduction. The findings offer a mechanism by which a single, brief odor stimulus can be translated into long-lasting intracellular changes that could play an important role in the perceptual adaptation to odors, and explain the longstanding puzzle that the olfactory CNG channels can be gated by both cAMP and cGMP.

Calcium Entry through Cyclic Nucleotide-Gated Channels in Individual Cilia of Olfactory Receptor Cells: Spatiotemporal Dynamics

“…6) fits well with results from previous work indicating that cGMP-dependent Ca 2ϩ entry plays a significant role in a longlasting form of odor adaptation (Zufall and Leinders-Zufall, 1997). The main difference between cAMP and cGMP-dependent Ca 2ϩ entry seems to be in the time course of the signals.…”

“…Removal of extracellular Ca 2ϩ results in a less transient cAMP-induced whole-cell current and eliminates the phasic-tonic behavior of odor currents during maintained stimulation (Kurahashi, 1990;Kurahashi and Shibuya, 1990;Zufall et al, 1991b;Kurahashi and Menini, 1997). Ca 2ϩ -dependent feedback regulation also can be initiated by the CO/ cGMP signaling system (Verma et al, 1993;Ingi and Ronnett, 1995;Leinders-Zufall et al, 1995a), which leads, via persistent activation of CNG channels by cGMP, to the induction of a long-lasting form of odor adaptation Zufall and Leinders-Zufall, 1997). Collectively, these results reveal complex effects of [Ca 2ϩ ] i in ORNs.…”

“…Given that cGMP mediates the induction of a long-lasting form of odor adaptation (Leinders- Zufall and Leinders-Zufall, 1997), interest has focused on the mechanisms by which cGMP elevation leads to olfactory adaptation. Because the build-up of cGMP in ORNs is slow, reaches only low micromolar levels, and can outlast the primary cAMP-mediated odor response for minutes (Breer et al, 1992;Verma et al, 1993;Leinders-Zufall et al, 1995a), endogenous odor-stimulated cGMP formation results in currents through CNG channels with small amplitudes but minute-long time courses Zufall and Leinders-Zufall, 1997). We have hypothesized that ionic flux through these persistent currents causes significant Ca 2ϩ accumulation in olfactory cilia as part of Ca 2ϩ -dependent feedback regulation.…”

“…Detection of Ca 2ϩ transients in individual cilia is of particular interest with respect to the mechanisms of sensory adaptation in ORNs. Elevated [Ca 2ϩ ] i governed by the activity of CNG channels plays important roles in feedback control of the sensitivity of olfactory transduction and is involved in a variety of specific regulatory functions such as desensitization during sustained stimulation (Kurahashi and Shibuya, 1990;Zufall et al, 1991b), rapid termination and recovery of the primary odor response (Kurahashi, 1989), and initiation of long-term adaptation (Zufall and Leinders-Zufall, 1997). Although many of the specific mechanisms and consequences triggered by Ca 2ϩ entry remain to be investigated, it is clear from previous work that elevated [Ca 2ϩ ] i can influence the activity of several molecular components of the cAMP pathway, including adenylyl cyclase (Sklar et al, 1986;Anholt and Rivers, 1990;Jaworski et al, 1995), CNG channels Kramer and Siegelbaum, 1992;Chen and Yau, 1994;Lynch and Lindemann, 1994), calmodulin-dependent phosphodiesterase (Borisy et al, 1992;Yan et al, 1995), Ca 2ϩ -activated Cl Ϫ channels (Kleene, 1993;Kurahashi and Yau, 1993;Lowe and Gold, 1993b;Zhainazarov and Ache, 1995), and Ca 2ϩ -activated K ϩ channels (Morales et al, 1995).…”

Carbon monoxide in biological systems: an experimental and clinical study

“…The mechanisms underlying learning and memory may also be affected by CO: it could act as a retrograde messenger which links post and presynaptic sites (Wu & Wang, 2005). In salamander olfactory receptor neurons it has been shown that CO regulates long-term adaptation to odorant stimulation via its effect on cGMP levels (Zufall & Leinders-Zufall, 1997). Regarding studies on signal substances involved in pain, CO has been demonstrated to be involved in the regulation of neuropathic pain in mice (Li & Clark, 2003).…”