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...
Control of global histone acetylation status is largely governed by the opposing enzymatic activities of histone acetyltransferases and deacetylases (HDACs).HDACs were originally identified as modulators of nuclear histone acetylation status and have been linked to chromosomal condensation and subsequent gene repression. Accumulating evidence highlights HDAC modification of non-histone targets. Mitochondria were first characterized as intracellular organelles responsible for energy production through the coupling of oxidative phosphorylation to respiration. More recently, mitochondria have been implicated in programmed cell death whereby release of pro-apoptotic inner membrane space factors facilitates apoptotic progression. Here we describe the novel discovery that the nuclear encoded Class II human histone deacetylase HDAC7 localizes to the mitochondrial inner membrane space of prostate epithelial cells and exhibits cytoplasmic relocalization in response to initiation of the apoptotic cascade. These results highlight a previously unrecognized link between HDACs, mitochondria, and programmed cell death.Originally identified as negative regulators of nuclear histone acetylation, HDACs 1 have been intimately linked to chromatin condensation and subsequent gene repression (1). More recently, increasing evidence has demonstrated HDAC modification of non-histone substrates (2-4) and an involvement in a broader array of biological events including apoptosis (5-8) and radiation sensitivity (9). Human Class I HDACs are generally nuclear proteins homologous to the yeast protein Rpd3 (HDAC1, -2, -3, and -8). Class II HDACs (HDAC4, -5, -6, -7, and -9) are related to HDA1 and often demonstrate regulated nucleocytoplasmic flux. Class III HDACs are structurally and phylogenetically distinct, being most similar to the NAD ϩ -dependent yeast SIR2 proteins.HDAC7 is a nuclear encoded Class II HDAC having a conserved C-terminal catalytic domain and a large, highly divergent N-terminal domain implicated in muscle differentiation (10). Cytoplasmic sequestration of HDAC7 can be enhanced by 14-3-3 protein interactions (11) and observed during T cell receptor-mediated apoptosis (8).Mitochondria were first characterized as intracellular organelles responsible for energy production through the coupling of oxidative phosphorylation to respiration. More recently, mitochondria have been implicated in genetically programmed cell death (12) whereby release of pro-apoptotic mitochondrial inner membrane space factors (13) facilitates the progression of the apoptotic cascade. Dysregulation of the mitochondrial apoptotic program has been linked to both enhanced cell death (14) as well as hyperproliferative growth (15).Here we describe the novel discovery that the nuclear encoded Class II human histone deacetylase HDAC7 localizes to the mitochondrial inner membrane space (IMS) of several human cell lines, in particular, prostate cancer epithelial cells. Upon induction of the apoptotic cascade, HDAC7 is released from mitochondria and, along with n...
We report the identification of two novel families of odorant receptor (OdR)-like proteins, termed spermatid chemoreceptors (SCRs), in rat spermatids of the testis. The full-length genomic clones encode seven transmembrane domain receptors that share 35-40% identity with certain OdRs and are among the most divergent members of the OdR superfamily based on phylogenetic analysis. RNase protection assays and in situ hybridization studies confirmed the expression of SCRs in spermatids, the post-meiotic, differentiating cell population in the testis. SCR transcripts were undetectable in the prepubertal testis but were readily identified in spermatids of sexually maturing and mature testis. Rapid amplification of cDNA end-polymerase chain reaction and genomic clone sequencing led to the discovery that SCRs are spliced upstream of their presumptive starting methionines. 5-Splicing of OdRs may regulate the expression of functional chemoreceptors.
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