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Biomedical subjects

G H Gold

Publications and source records attributed to G H Gold.

At least 19 recordsLinked to original sources
PubMed2000

Disruption of the type III adenylyl cyclase gene leads to peripheral and behavioral anosmia in transgenic mice.

Cyclic nucleotide-gated ion channels in olfactory sensory neurons (OSNs) are hypothesized to play a critical role in olfaction. However, it has not been demonstrated that the cAMP signaling is required for olfactory-based behavioral responses, and the contributions of specific adenylyl cyclases to olfaction have not been defined. Here, we report the presence of adenylyl cyclases 2, 3, and 4 in olfactory cilia. To evaluate the role of AC3 in olfactory responses, we disrupted the gene for AC3 in mice. Interestingly, electroolfactogram (EOG) responses stimulated by either cAMP- or inositol 1,4,5-triphosphate- (IP3-) inducing odorants were completely ablated in AC3 mutants, despite the presence of AC2 and AC4 in olfactory cilia. Furthermore, AC3 mutants failed several olfaction-based behavioral tests, indicating that AC3 and cAMP signaling are critical for olfactory-dependent behavior.

Adenylyl Cyclases↗
PubMed2000

Formation of precise connections in the olfactory bulb occurs in the absence of odorant-evoked neuronal activity.

Olfactory neurons expressing the same odorant receptor converge to a small number of glomeruli in the olfactory bulb. In turn, mitral and tufted cells receive and relay this information to higher cortical regions. In other sensory systems, correlated neuronal activity is thought to refine synaptic connections during development. We asked whether the pattern of connections between olfactory sensory axons and mitral cell dendrites is affected when odor-evoked signaling is eliminated in mice lacking functional olfactory cyclic nucleotide-gated (CNG) channels. We demonstrate that olfactory sensory axons converge normally in the CNG channel mutant background. We further show that the pruning of mitral cell dendrites, although slowed during development, is ultimately unperturbed in mutant animals. Thus, the olfactory CNG channel-and by inference correlated neural activity--is not required for generating synaptic specificity in the olfactory bulb.

Animals↗
PubMed1999

Controversial issues in vertebrate olfactory transduction.

A number of controversial issues in olfactory transduction are discussed including the matter of multiple transduction pathways, with a new experiment proposed. Evidence is reviewed concerning the fact that cyclic AMP is the only pathway mediating olfactory transduction. Two knockout mice have been produced: a knockout for a cyclic nucleotide-gated channel and a G(olf) knockout. The results obtained with both mice are consistent with cyclic AMP being the only second messenger. The evidence for gaseous second channel messengers is also reviewed. Slow gating kinetics of the cyclic nucleotide-gated channel and the detection of single-odorant molecules are reviewed. A new phenomenon in which odorants can block odorant responses is discussed.

Animals↗
PubMed1998

Mice deficient in G(olf) are anosmic.

We have used gene targeting to examine the role of the G alpha subunit, G(olf), in olfactory signal transduction. Mice homozygous for a null mutation in G(olf) show a striking reduction in the electrophysiological response of primary olfactory sensory neurons to a wide variety of odors. Despite this profound diminution in response to odors, the topographic map of primary sensory projections to the olfactory bulb remains unaltered in G(olf) mutants. Greater than 75% of the G(olf) mutant mice are unable to nurse and die within 2 days after birth. Rare surviving homozygotes mate and are fertile, but mutant females exhibit inadequate maternal behaviors. Surviving homozygous mutant mice also exhibit hyperactive behaviors. These behavioral phenotypes, taken together with the patterns of G(olf) expression, suggest that G(olf) is required for olfactory signal transduction and may also function as an essential signaling molecule more centrally in the brain.

Animals↗
PubMed1996

General anosmia caused by a targeted disruption of the mouse olfactory cyclic nucleotide-gated cation channel.

Olfactory neurons transduce the binding of odorants into membrane depolarization. Two intracellular messengers, cyclic AMP (cAMP) and inositol trisphosphate (IP3), are thought to mediate this process, with cAMP generating responses to some odorants and IP3 mediating responses to others. cAMP causes membrane depolarization by activating a cation-selective cyclic nucleotide-gated (CNG) channel. We created a mutant "knockout" mouse lacking functional olfactory CNG channels to assess the roles of different second messenger pathways in olfactory transduction. Using an electrophysiological assay, we find that excitatory responses to both cAMP- and IP3-producing odorants are undetectable in knockout mice. Our results provide direct evidence that the CNG channel subserves excitatory olfactory signal transduction, and further suggest that cAMP is the sole second messenger mediating this process.

Animals↗
PubMed1995

Olfactory transduction is intrinsically noisy.

The sources of noise that limit olfactory signal detection were investigated in dissociated rat olfactory receptor cells. Near-threshold odorant-evoked currents exhibited large random fluctuation. However, similar fluctuations were observed in the absence of applied odorants when currents were induced by elevating the intracellular cyclic AMP concentration. This suggests that the fluctuations reflect noise intrinsic to the transduction mechanism, rather than the quantal nature of an odorant stimulus. For many odorants, this intrinsic noise may preclude the reliable detection of single odorant molecules.

1-Methyl-3-isobutylxanthine↗
PubMed1994

Suppression of odorant responses by odorants in olfactory receptor cells.

Odorants activate an inward current in vertebrate olfactory receptor cells. Here it is shown, in receptor cells from the newt, that odorants can also suppress this current, by a mechanism that is distinct from inhibition and adaptation. Suppression provides a simple explanation for two seemingly unrelated phenomena: the anomalously long latency of olfactory transduction and the existence of an "off response" at the end of a prolonged stimulus. Suppression may influence the perception of odorants by masking odorant responses and by sharpening the odorant specificities of single cells.

Acetophenones↗
PubMed1993

Nonlinear amplification by calcium-dependent chloride channels in olfactory receptor cells.

The sense of smell is highly evolved in mammals, allowing discrimination between a vast number of odorants, with detection thresholds as low as 10(-17) M (ref. 1). Although several features of mammalian olfactory transduction have been revealed by biochemical and molecular biological studies, the odorant-induced membrane current has remained elusive. In amphibians this current is mediated by cyclic-nucleotide-gated channels, which depolarize the cell by Na+ and Ca+ influx and consequent Cl- efflux through Ca(2+)-dependent Cl- channels. The Cl- current may be absent in mammals, however, because its proposed role is linked to the aquatic habitat of amphibians. Here we show that the transduction current in rat olfactory receptor cells is initiated by cyclic-nucleotide-gated channels. The Cl- current is also present and endows the transduction current with a steep sigmoidal dependence on cyclic AMP concentration in both rat and in an amphibian, indicating a new function for the Cl- channel: nonlinear amplification of the transduction signal, whereby suprathreshold responses are boosted relative to basal transduction noise.

Amphibians↗
PubMed1993

Induction of olfactory receptor sensitivity in mice.

Repeated exposure to olfactory ligands (odorants) increased peripheral olfactory sensitivity in mice. For two unrelated ligands, androstenone and isovaleric acid, induction of olfactory sensitivity was odorant-specific and occurred only in inbred strains that initially had low sensitivity to the exposure odorant. These data demonstrate stimulus-induced plasticity in a sensory receptor cell, suggesting a form of stimulus-controlled gene expression. Induction with two unrelated odorants implies that olfactory induction is a general phenomenon that may occur in a large fraction of the human population.

Androstenes↗
PubMed1993

Contribution of the ciliary cyclic nucleotide-gated conductance to olfactory transduction in the salamander.

1. Flash photolysis of caged cyclic nucleotides was used to examine the contribution of the ciliary cyclic nucleotide-gated conductance to olfactory transduction in the tiger salamander. Brief illumination of solitary olfactory receptor cells loaded with 100 microM caged cyclic AMP caused a large inward current (peak amplitude 355 +/- 200 pA; mean +/- S.D. for eleven cells) under whole-cell voltage clamp at -50 mV. 2. The photolysis response was initiated after a latency of 4-12 ms, whereas an odorant response of identical amplitude had a latency of several hundred milliseconds. The amplitudes of both responses exhibited almost identical voltage dependence between -50 and +25 mV, with both reversing near 0 mV. The time courses of the falling phases of odorant and photolysis responses also exhibited similar voltage dependence, both being prolonged at positive voltages. 3. Photolysis of caged cyclic GMP activated a current similar in amplitude and time course to that produced by photolysis of caged cyclic AMP. 4. When the flash was spatially limited to the cilia, the amplitude and duration of the photolysis response increased linearly with the length of the cilia illuminated (for cilia not longer than 30-40 microns) while the latency remained constant at 4-12 ms. The increase in duration was described semi-quantitatively by a model which incorporated diffusion and saturable hydrolysis of cyclic AMP. When the flash was limited to the soma or proximal dendrite, the response latency was proportional to the square of the distance between the illuminated region and the cilia. 5. Dialysis of cells with 500 microM cyclic AMP from a whole-cell electrode under voltage clamp activated a large transient inward current. Simultaneous suction electrode recording showed that this current originated almost entirely from the ciliary membrane. The density of cyclic nucleotide-gated channels was estimated to be 800-fold higher in the cilia than in the soma. 6. Summation of simultaneous odorant and photolysis responses was non-linear, the flash-induced current being enhanced during a small odorant response and attenuated during a large odorant response. Summation of two photolysis responses was similarly non-linear. The data were consistent with odorant stimuli and cyclic AMP both activating a common cyclic nucleotide-gated conductance with a Hill coefficient, n, of 2.0-4.4. For n = 2.5, the basal cyclic AMP concentration was estimated to be less than 20% of the K 1/2, which predicts a basal current of 5.8 pA, less than 2% of the maximum.(ABSTRACT TRUNCATED AT 400 WORDS)

Ambystoma↗
PubMed1991

The spatial distributions of odorant sensitivity and odorant-induced currents in salamander olfactory receptor cells.

1. Suction electrode and whole-cell recording were used to record membrane currents from defined regions of solitary olfactory receptor cells from Ambystoma tigrinum. 2. Under whole-cell current clamp, stimulation of cells with odorants activated an inward current in the cilia, an outward current in the soma, and induced a membrane depolarization. Clamping the membrane potential at its resting value of -70 mV increased the inward ciliary current 5- to 10-fold and abolished the outward somatic current. 3. Local odorant stimulation was accomplished by ejecting an odorant solution into a steady flow of Ringer solution. A suction electrode was used to immobilize a cell in the flow and to record the odorant-induced somatic current. The amplitude of the odorant response increased approximately linearly with the length of cilia exposed to the stimulus, but was independent of the length of dendrite exposed to the stimulus, indicating that odorant sensitivity is predominantly localized to the cilia. 4. The latencies of responses recorded under flow did not vary with the region of the cilia which was exposed to the stimulus. Also, the magnitude of the inward ciliary current activated by odorants was equal to that of the whole-cell current recorded under voltage clamp. These observations indicate that the odorant-induced inward current is predominantly localized to the ciliary membrane. 5. Under whole-cell current clamp, local application of a high-K+ solution generated an outward somatic current when applied to the dendrite, but had no effect when applied to the cilia. This indicates that the density of the resting K+ conductance is lower in the ciliary membrane than in the dendritic membrane. 6. The results above are consistent with the hypothesis that all components of the transduction mechanism are uniformly distributed within the cilia, and that the cilia are electrotonically compact, even during an odorant-induced conductance increase.

Ambystoma↗
PubMed1989

Adenylate cyclase mediates olfactory transduction for a wide variety of odorants.

An odor-stimulated adenylate cyclase [ATP pyrophosphate-lyase (cyclizing), EC 4.6.1.1] is thought to mediate olfactory transduction in vertebrates. However, it is not known whether the adenylate cyclase serves this function for all odorants or for only certain classes of odorants. To investigate this question, we have compared the abilities of 35 odorants to stimulate the adenylate cyclase and to elicit an electrophysiological response. We report a strong positive correlation between the magnitude of adenylate cyclase stimulation and the summated electrical response of the olfactory epithelium (electro-olfactogram) evoked by individual odorants. We also show that the adenylate cyclase stimulator forskolin equally attenuates the electro-olfactogram response for all odorants tested. These data provide evidence that the adenylate cyclase mediates transduction for a wide variety of odorants.

Adenylyl Cyclases↗
PubMed1986

Plasma membrane calcium fluxes in intact rods are inconsistent with the "calcium hypothesis".

The temporal relationship between the extracellular rod photovoltage and light-induced net Ca fluxes across the rod plasma membrane is investigated. The net Ca flux measurements are derived from extracellular Ca concentration measurements at the receptor surface of the isolated bullfrog retina. As reported previously, illumination leads to a net Ca efflux, which is followed by a net influx, during which the released Ca is taken back up. However, the net Ca flux has two characteristics that are inconsistent with the hypothesis that intracellular free Ca is the intracellular messenger for phototransduction in rods. First, during maintained photovoltage saturation, the net Ca efflux is transient, declining with a stereotypic time course that is independent of stimulus intensity and duration. Second, the significant rate of net influx during Ca uptake has no correlate in the photovoltage waveform. These observations are not consistent with the "Ca hypothesis." Rather, these data corroborate recent findings suggesting that light causes a decrease rather than an increase in intracellular free Ca concentration.

Animals↗
PubMed1980

Light-induced calcium release by intact retinal rods.

Brief illumination of the isolated toad retina produces a transient increase in the extracellular free Ca concentration in the photoreceptor layer. This change in concentration arises from the release of Ca2+ by the rod outer segments. The release begins within 200 msec after the stimulus flash. The peak amplitude of the concentration change increases linearly with light intensity up to approximately 100 absorbed photons per rod and saturates at about 10(7) absorbed photons per rod. In the linear range, the amount of Ca released corresponds to about 2 x 10(4) Ca2+ per absorbed photon per rod. The high stoichiometry of this release, in relation to the low free intracellular Ca concentration, suggests that the release reflects a light-dependent increase in the intracellular free Ca concentration. This light-activated Ca release occurs in the absence of a detectable receptor potential (in low-Na Ringer's solution) and, therefore, must reflect one of the initial stages in the transduction process.

Animals↗