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Biomedical subjects

J Lisman

Publications and source records attributed to J Lisman.

13 recordsLinked to original sources
PubMed1992

Deactivation of visual transduction without guanosine triphosphate hydrolysis by G protein.

G proteins couple receptors to their target enzymes in many signal transduction cascades. It has generally been thought that deactivation of such cascades cannot occur without the hydrolysis of guanosine triphosphate (GTP) by G protein. This requirement has now been reexamined in both vertebrate and invertebrate phototransduction. Results indicate that GTP hydrolysis is not required for deactivation. Evidence is presented for an alternative model in which the target enzyme is deactivated by an inhibitory factor that is available even when GTP hydrolysis is blocked.

Animals↗
PubMed1992

Mechanisms of amplification, deactivation, and noise reduction in invertebrate photoreceptors.

In this review we have discussed the problem of deactivation at both the rhodopsin and G protein levels. Of particular interest is the novel observation that rhodopsin deactivation can be modulated by light. This modulation is likely to play an important role in light adaptation by reducing the gain of transduction. One interesting possibility is that this modulation involves the phosphorylation of an arrestin-like molecule, but this remains to be tested. One of the experimental advantages of Limulus photoreceptors is the large size of the single photon responses and the fact that even single G proteins produce a detectable response. This made possible the observation that nonhydrolyzable GTP analogues produce discrete transient events rather than the step-like events that would be predicted by previous models. This observation led us to a new view of how enzyme deactivation is coupled to GTP hydrolysis on G protein. According to this view, enzymes are activated by G protein, but can be deactivated by processes that are not dependent on G protein or the hydrolysis of GTP. We have conducted several types of experiments, including some on the vertebrate rod system, that strongly support this hypothesis. A second major theme of this review is transduction noise. The available biochemical evidence suggests that both G protein and G protein-activated enzymes are likely to become spontaneously active and generate undesirable noise. Our measurements indicate, however, that this noise is orders of magnitude smaller than would be predicted by simple models, suggesting that special mechanisms must exist for suppressing this noise. We have proposed a specific mechanism by which enzymes regulated allosterically by multiple subunits could act as coincidence detectors to reduce transduction noise. Finally, there is the fundamental question of which second messengers have a direct role in invertebrate phototransduction. After Fesenko et al. (1985) showed that the light-dependent conductance in vertebrate rods was modulated by cGMP and not by Ca2+, there was rapid progress in understanding the vertebrate photoreceptor transduction mechanism. Now that it has been established that invertebrate light-dependent channels are regulated by cGMP and not by Ca2+, we can expect rapid progress in understanding invertebrate phototransduction. A key question that needs to be answered is whether the InsP3-Ca2+ pathway somehow triggers changes in cGMP or whether there is an altogether different pathway by which cGMP metabolizing enzymes are affected by light.

Adaptation, Physiological↗
PubMed1991

Muscarinic suppression of the M-current is mediated by a rise in internal Ca2+ concentration.

The role of intracellular Ca2+ in the muscarinic suppression of M-current was examined. Intracellular injection of Ca2+ buffer into cells in the intact ganglion reduced the response to muscarinic agonist. In similar experiments on isolated cells, Ca2+ buffer was introduced into the cytoplasm using a perfused recording pipette. Ca2+ buffer (20 mM) with the free Ca2+ concentration set to normal resting levels produced a reversible reduction of the muscarinic response. In a second line of investigation, it was found that pharmacological procedures designed to deplete internal stores of Ca2+ produced a decrease in the muscarinic response. These results, taken together with previous work, support the hypothesis that the muscarinic suppression of M-current is mediated by the release of Ca2+ from intracellular stores.

Animals↗
PubMed1989

A mechanism for the Hebb and the anti-Hebb processes underlying learning and memory.

In a previous paper, a model was presented showing how the group of Ca2+/calmodulin-dependent protein kinase II molecules contained within a postsynaptic density could stably store a graded synaptic weight. This paper completes the model by showing how bidirectional control of synaptic weight could be achieved. It is proposed that the quantitative level of the activity-dependent rise in postsynaptic Ca2+ determines whether the synaptic weight will increase or decrease. It is further proposed that reduction of synaptic weight is governed by protein phosphatase 1, an enzyme indirectly controlled by Ca2+ through reactions involving phosphatase inhibitor 1, cAMP-dependent protein kinase, calcineurin, and adenylate cyclase. Modeling of this biochemical system shows that it can function as an analog computer that can store a synaptic weight and modify it in accord with the Hebb and anti-Hebb learning rules.

Adenylyl Cyclases↗
PubMed1987

Nontransducing rhodopsin.

Rhodopsin is converted by light to an active photoproduct that triggers the transduction cascade. The active photoproduct must then be inactivated by some kind of chemical modification. The question addressed here is whether photoconversion of the inactive photoproduct to rhodopsin creates a modified form of rhodopsin that is unable to support transduction. This question was investigated in ultraviolet receptors of Limulus median eye by measuring the relative quantum efficiency of excitation after photoregeneration of rhodopsin from the inactive photoproduct. The results show that when this newly created rhodopsin absorbs a photon, no receptor potential is generated; i.e., the pigment is nontransducing. A dark process requiring 30-60 min returns rhodopsin to its transducing form.

Animals↗
PubMed1985

The effect of nucleotides on the rate of spontaneous quantum bumps in Limulus ventral photoreceptors.

The effect of intracellular nucleotides on the rate of spontaneous quantum bumps in Limulus ventral photoreceptors has been examined. Internal dialysis of photoreceptors with solutions lacking nucleotide leads to an elevation of the quantum bump rate that can be reversed by introduction of nucleotide. Similarly, elevation occurs after treating intact cells with the metabolic inhibitor 2-deoxyglucose. This effect can be reversed by intracellular injection of ATP. The rate of spontaneous quantum bumps in unpoisoned cells can be reduced to below normal levels by injection of ATP. These results support the hypothesis that high-energy nucleotides suppress the rate of spontaneous quantum bumps.

Alkaline Phosphatase↗
PubMed1985

The role of metarhodopsin in the generation of spontaneous quantum bumps in ultraviolet receptors of Limulus median eye. Evidence for reverse reactions into an active state.

The origin of spontaneous quantum bumps has been examined in the ultraviolet photoreceptors of Limulus median eye. These cells have a rhodopsin with a lambda max at 360 nm and a stable photoproduct, metarhodopsin, with a lambda max at 470 nm. The steady state rate of spontaneous quantum bumps was found to be higher when the metarhodopsin concentration was high than when the rhodopsin concentration was high. This result implicates metarhodopsin in the generation of spontaneous quantum bumps. Furthermore, this result is consistent with the idea that the reaction which inactivates metarhodopsin (terminates the ability of metarhodopsin to initiate the reactions leading to a quantum bump) is reversible and that such reversions can be a significant source of spontaneous quantum bumps. Given that the rate of spontaneous quantum bumps is approximately 1/s under conditions where the number of inactive metarhodopsin molecules is approximately 10(9), it follows that the molecular switch that inactivates metarhodopsin reverses with a probability of less than 10(-9). A model is presented of how a molecular switch with this reliability might be constructed.

Animals↗
PubMed1984

Calcium mediates the light-induced decrease in maintained K+ current in Limulus ventral photoreceptors.

In addition to increasing the conductance to sodium, light reduces the maintained voltage-dependent potassium current (iK) in Limulus ventral photoreceptors. We have investigated the mechanism underlying this long-lasting decrease in ik. Intracellular injection of calcium produced a similar reduction of the voltage-dependent outward current. This reduction was not due to an activation of the voltage-dependent inward current (iin) because calcium injection reduced the outward current even under conditions where iin was blocked with Ni2+, and because calcium injection produced a decrease in conductance, as measured from the slope of the instantaneous i-V curve. The effect of light on ik could be blocked by injection of the calcium buffer EGTA (pCa 7.1) to an intracellular concentration of 50-70 mM. Even larger injections of the pH buffer MOPS (100-200 mM) did not reduce the effect of light on ik. These experiments show that intracellular free calcium (Cai2+) can reduce ik. Furthermore, since Cai2+ is known to increase in light, our results are consistent with the hypothesis that calcium is the internal transmitter for the light-induced decrease in ik.

Animals↗
PubMed1984

Light reduces the voltage-dependent inward current in Limulus ventral photoreceptors.

In Limulus ventral photoreceptors, illumination not only increases a specialized light-activated sodium conductance but also modulates voltage-dependent conductances. Previous work has demonstrated that the delayed rectifier current is reduced by light; we report here that the early voltage-dependent inward current is also reduced by light. Furthermore, by maintained during continuous depolarization and that this maintained inward current can be reduced by light. EGTA injection was found to increase the maintained inward current.

Animals↗
PubMed1978

Initiation of light adaptation in barnacle photoreceptors.

Intracellular recordings were used to measure the action spectrum of light adaptation in barnacle photoreceptors. The action spectrum closely resembles the absorption spectrum of rhodopsin (lambdamax at 530 nanometers) and is clearly different from that of metarhodopsin (lambdamax at 495 nanometers). These results suggest that absorption of light by rhodopsin initiates both excitation and light adaptation. The previously reported antagonistic process initiated by metarhodopsin does not appear to play a role at moderate light intensities.

Adaptation, Physiological↗
PubMed1975

Localized desensitization of Limulus photoreceptors produced by light or intracellular calcium ion injection.

Spots of light were used to measure the light sensitivity of spatially separated regions of single Limulus photoreceptors. The desensitization caused by irradiating part of the cell was largest in the irradiated region. The desensitization caused by intracellular calcium ion injection was largest near the infection site. The spread of desensitization away from the injection site suggests that calcium ion can diffuse over neuronal dimensions, but that the effective rate of diffusion is not so high as to abolish calcium gradients. The results are compatible with the previously proposed hypothesis that a rise in the intracellular calcium ion concentration mediates light adaptation.

Animals↗
PubMedDate not supplied

Evaluation of a model of long-term memory based on the properties of the Ca2+/calmodulin-dependent protein kinase.

1.) This paper further explores the feasibility of a model for long-term memory (Lisman, 1985; Lisman and Goldring, 1988). According to this model, the value of synaptic efficacy of individual synapses is stored locally by the group of Ca2+/calmodulin-dependent protein kinase II molecules contained within the post-synaptic density. 2.) Calculations presented in a previous paper indicate that it is feasible for these kinase molecules to encode information with the stability required for long-term memory. These calculations were based on the assumption that the 30 phosphorylation sites on the enzyme are phosphorylated in a serial fashion, i.e. that the sites are not independent. This paper presents similar calculations based on the alternative assumption that the sites are phosphorylated independently. 3.) Kinase molecules that have been switched "on" undergo a continuous process of dephosphorylation and rephosphorylation. Estimates of the energy consumed by this cycle indicate that the energy required would not make unreasonable demands on neuronal metabolism. The necessity of energy consumption by molecular switches is discussed. 4.) The rate of intramolecular autophosphorylation of the Ca2+/calmodulin dependent kinase implies that the cytoplasmic free Ca2+ concentration must stay elevated for several seconds in order for kinase molecules to switch "on". How such a sustained rise in Ca2+ might be achieved is discussed. 5.) An alternative view is that long-term memory storage involves a change in gene expression. The principal evidence supporting this view is the effect of protein synthesis inhibitors on memory. A model is presented showing that the observed effect of protein synthesis inhibitors does not necessarily imply that information storage is at the level of gene expression. 6.) The distinction between "presynaptic" and "postsynaptic" associative learning mechanisms is discussed. It is concluded that this distinction can be misleading and that the possibility that the underlying mechanisms are similar should not be excluded.

Calcium↗