Biomedical subjects
Publications and source records attributed to M Nirenberg.
Neurons dissociated from chick embryo retina and cultured from more than 1 x 10(8) synapses per mg of protein. At least three types of synapses are synthesized which resemble those of the intact retina. In addition, two populations of neurons were found, those with nicotinic acetylcholine receptors and those without the receptors.
Incubation of neuroblastoma X glioma hybrid cells for 12-97 hr with methionine-enkephalin results in an increase in adenylate cyclase activity [ATP pyrophosphate-lyase (cyclizing), EC 4.6.1.1] that is mediated by the opiate receptor. The results show that cells become tolerant to, and dependent upon, enkephalin.
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Clonal mouse neuroblastoma cells without tyrosine 3-monooxygenase [EC 1.14.16.2; tyrosine hydroxylase; L-tyrosine, tetrahydropteridine:oxygen oxidoreductase (3-hydroxylating)] activity were fused with normal cells from embryonic mouse sympathetic ganglia. One of the 37 hybrid cell lines obtained possesses high tyrosine 3-monooxygenase activity and synthesizes dopamine. These cells also have excitable membranes and generate action potentials in response to electrical stimuli. Thus hybrid cells, generated by fusion of neuroblastoma cells with normal cells from the nervous system, can acquire neural properties not found with the parental neuroblastoma cells.
Morphine inhibits adenylate cyclase (EC 4.6.1.1) activity of neuroblastoma times glioma hybrid cells. The inhibition is stereospecific and is reversed by the antagonist, naloxone. The relative affinities of narcotics for the opiate receptor agree well with their effectiveness as inhibitors of adenylate cyclase. Morphine-sensitive and -insensitive cell lines were found, and the degree of sensitivity was shown to be dependent upon the abundance of narcotic receptors. Thus, morphine receptors are functionally coupled to adenylate cyclase. A molecular mechanism for narcotic addiction and tolerance is proposed.
Narcotics affect adenylate cyclase [ATP pyrophosphate-lyase (cyclizing), EC 4.6.1.1] in two opposing ways, both mediated by the opiate receptor. The first process is the readily reversible inhibition of the enzyme by narcotics; the second is a compensatory increase in enzyme activity which is delayed in onset and relatively stable. Late positive regulation of the enzyme counteracts the inhibitory influence of morphine and is responsible for narcotic dependence and tolerance. The coupled inhibitory and positive regulatory mechanisms for adenylate cyclase provide a means of activating and deactivating neural circuits hours after the initial event and thus may play a role in a memory process.
3':5'-cGMP levels of neuroblastoma N1E-115 cells increase as much as 200-fold upon activation of muscarinic acetylcholine receptors, resulting in intracellular cGMP concentrations greater than 600 pmol/mg of protein. The cells also have receptors for adenosine which mediate an increase in 3':5'-cAMP levels. Unexpectedly, prostaglandin E1 was found to increase the concentrations of both cGMP and cAMP. Carbamylcholine, adenosine, and PGE1 were added to cells separately and in pairs to determine the effect of one compound on cell responses to another. Reciprocal inhibition, unilateral inhibition, additive, and nonadditive responses were observed with respect to cGMP and cAMP levels when different pairs of receptors were activated simultaneously.
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A neuroblastoma x glioma hybrid cell line with well-developed neural properties was found that has high-affinity morphine receptors. The average cell contains approximately 3 x 10(6) receptors. In contrast, parent cells and other neuroblastoma or hybrid cell lines tested had few or no morphine receptors.
Veratridine, an activator of action potential Na(+) ionophores, stimulated passive Na(+) uptake by electrically excitable neuroblastoma and muscle cells but had no effect on clonal cell lines defective in Na(+)-ionophore activity. Veratridine-dependent Na(+) uptake was completely inhibited by tetrodotoxin, a specific inhibitor of the action potential Na(+) ionophore. Half-maximal inhibition was obtained with 11 nM tetrodotoxin. Thus, veratridinedependent Na(+) uptake provides a specific and convenient means of assaying populations of cultured cells for action potential Na(+)-ionophore activity.
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Neuroblastoma clones were examined for choline acetyltransferase (EC 2.3.1.6), tyrosine hydroxylase (EC 1.14.3.a), acetylcholinesterase (EC 3.1.1.7), and also for neurite formation. One clone does not form axons or dendrites. Three types of clones were found with respect to neurotransmitter synthesis: cholinergic, adrenergic, and clones that do not synthesize acetylcholine or catechols. All clones contain acetylcholinesterase. These results show that genes determining neurotransmitter species can be expressed in dividing cells, that the parental programs of gene expression are inherited, and that dividing cells can be programmed with respect to their ability to communicate with other cells.
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Neuroblastoma cells with electrically excitable membranes were fused with electrically passive L cells having a hitherto undescribed electrical marker. Hybrid cells, examined 10-40 generations after fusion, were found to be electrically excitable. The results show that at least a part of the genetic information for neuron differentiation can be functionally expressed in N x L hybrid cells. Evidence for the regulation of action potential components was also found.
The effects of potential neurohormones on the intracellular concentrations of adenosine 3':5'-cyclic monophosphate have been examined with three clonal lines of cultured glial tumors. In all cases, norepinephrine and isoproterenol produced striking elevations of the intracellular concentrations of the cyclic nucleotide. The response was mediated by a beta-adrenergic receptor. This effect is hypothesized to represent a molecular mechanism for neuronal-glial communication coupled to concurrent communication between neurons.