Functional Expression of the Heteromeric “Olfactory” Cyclic Nucleotide-Gated Channel in the Hippocampus: A Potential Effector of Synaptic Plasticity in Brain Neurons

Abstract

Cyclic nucleotide-gated (cng) channels are important components of signaling systems mediating sensory transduction. In vertebrate photoreceptors, light activates a signaling cascade that causes a decrease in intracellular cGMP concentrations, closing retinal cng channels. Signal transduction in olfactory receptor neurons is believed to proceed via G-proteinmediated elevation of intracellular cAMP in response to odorant binding by 7-helix receptors. cAMP opens the olfactory cng channel, which is highly permeable to Ca 2ϩ . Here we demonstrate by in situ hybridization and immunohistochemistry with subunit-specific antibodies that both subunits of the heteromeric rat olfactory cng channel are also widely expressed in the brain. Expression of the retinal rod cng channel, however, can be detected only in the eye. In the adult hippocampus, the olfactory cng channel is expressed on cell bodies and processes of CA1 and CA3 neurons. In cultured embryonic hippocampal neurons, the channel is localized to a subset of growth cones and processes. We recorded conductances with the electrophysiological characteristics of the heteromeric olfactory cng channel in excised inside-out patches from these cultured neurons. We also show that Ca 2ϩ influx into hippocampal neurons in response to cyclic nucleotide elevation can be detected using fura-2 imaging. Cyclic nucleotide elevation has been implicated in several mechanisms of synaptic plasticity in the hippocampus, and these mechanisms also require elevation of intracellular Ca 2ϩ . Our results suggest that the "olfactory" cng channel could regulate synaptic efficacy in brain neurons by modulating Ca 2ϩ levels in response to changes in cyclic nucleotide concentrations. Key words: cyclic nucleotide-gated channels; cAMP; cGMP; olfaction; sensory transduction; hippocampus; synaptic plasticityCyclic nucleotide-gated (cng) channels open in response to binding of the intracellular cyclic nucleotides cGMP and cAMP. They resemble voltage-gated channels, having six transmembrane domains and a pore region, but they also contain a cytoplasmic region with homology to the cyclic nucleotide binding domains of cGMP-and cAMP-dependent protein kinases (PKG and PKA). The native retinal rod and olfactory cng channels are believed to be heterotetramers composed of two different subunits. The ␣ subunits [also known in the rat as rRCNC1 (retinal) and rOCNC1 (olfactory)] can form homomeric channels (for review, see Zagotta and Siegelbaum, 1996). The ␤ subunits (rRCNC2 and rOCNC2) cannot form functional channels on their own, but they oligomerize with the ␣ subunits to create channels with modified properties (Chen et al., 1993;Bradley et al., 1994;Liman and Buck, 1994;Korschen et al., 1995). Unlike most voltage-gated and ligand-gated channels, cng channels do not exhibit desensitization but remain open continuously in the presence of cyclic nucleotide.The incorporation of the rOCNC2 subunit into the olfactory cng channel dramatically affects cyclic nucleotide sensitivity. The heteromeric rOCNC1/rOCNC2 c...

Importance of the CNGA4 channel gene for odor discrimination and adaptation in behaving mice

“…Given the role of the vomeronasal organ in modulation of sexual and social behaviors (30)(31)(32), interpretation of the performance in the behavioral tests used here should not be complicated by a potential function for CNGA4 in the vomeronasal organ. CNGA4 mRNA expression has also been described in the hippocampus and other brain regions (33), but the need for extensive PCR amplification and long development times for in situ hybridization suggests that the level of channel mRNA is very low (16,33). Our behavioral tests demonstrate that CNGA4 Ϫ/Ϫ mice do not display obvious dysfunctions in the number of sessions required to learn odordiscrimination tasks.…”

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

“…Finally, this approach should help to determine the precise functions of CNG channels expressed in other neurons of the nervous system (cf. Ahmad et al, 1994;Leinders-Zufall et al, 1995b;Kingston et al, 1996;Bradley et al, 1997).…”

Epac signaling is required for hippocampus-dependent memory retrieval

“…Thus, potentiation of HCN1 by cAMP might impair rather than facilitate retrieval. Finally, despite their existence for at least a decade, no cognitive phenotype has been described for mice genetically lacking CNG channels, including those expressed in the hippocampus (35)(36)(37)(38).…”