The hypothesis advanced in this article requires further validation. Undoubtedly it will require modification as our knowledge of biochemical control increases. Nevertheless, it should prove useful in focusing attention on the apparent similarity in the response of a large number of specific cell types to particular stimuli. Emphasis has been placed on a few common and apparently key elements in these responses. It is recognized that other factors are undoubtedly involved. Specifically, the changes in membrane potentials indicate the likelihood of widespread changes in the properties of the cell membrane, for example, changes in Na(+) and K(+) transport and distribution. These aspects of cellular responses may eventually prove to be of equal or greater importance than those common aspects of the system already identified.

Cell Communication, Calcium Ion, and Cyclic Adenosine Monophosphate

Since the discovery in 1957 that cyclic AMP acts as a second messenger for the hormone adrenaline, interest in this molecule and its companion, cyclic GMP, has grown Over a period of nearly 50 years, research into second messengers has provided a framework for understanding transmembrane signal transduction, receptor-effector coupling, protein-kinase cascades and downregulation of drug responsiveness The breadth and impact of this work is reflected by five different Nobel prizes

Cyclic nucleotide research — still expanding after half a century

Purification and properties of rabbit skeletal muscle adenosine 3',5'-monophosphate-dependent protein kinases.

Adenosine 3′,5′-monophosphate-dependent protein kinase activity was found in about thirty sources including many mammalian tissues as well as species representative of eight different invertebrate phyla. The data support a unifying theory for the mechanism of action of adenosine 3′,5′-monophosphate, namely that its many and diverse effects are mediated through activation of tissue-specific protein kinases.

https://www.pnas.org/content/pnas/64/4/1349.full.pdf

Cyclic nucleotide-dependent protein kinases, iv. widespread occurrence of adenosine 3′,5′-monophosphate-dependent protein kinase in various tissues and phyla of the animal kingdom

The postsynaptic actions of some neurotransmitters may be mediated through cyclic nucleotides and cyclic nucleotide-dependent phosphorylation of specific membrane proteins in postsynaptic cells. In addition to providing a molecular basis for the actions of several neurotransmitters and of certain drugs affecting behaviour, the model suggests a mechanism by which neurotransmitter signals may be converted into electrophysiological responses in postsynaptic cells.

Possible role for cyclic nucleotides and phosphorylated membrane proteins in postsynaptic actions of neurotransmitters

Adenosine cyclic 39,59-monophosphate at a concentration of 10-7M causes a four-to sixfold increase in the rate of histone phosphorylation catalyzed by a liver enzyme preparation. This observation suggests a mechanism for the induction of RNA synthesis by those hormones that cause increases in the concentration of cyclic AMP.

Histone Phosphorylation: Stimulation by Adenosine 3',5'-Monophosphate

Characterization of a Phosphatase Specific for Phosphorylated Histones and Protamine

Action of adenosine 3',5'-monophosphate-dependent histone kinase in vivo.

Studies of the action of protein kinases on substrates other than the enzymes involved in glycogen metabolism have been sporadic until quite recently. Early observations of protein kinase activity were made by Burnett and Kennedy,’ who showed that liver contains an enzyme that catalyzes the phosphorylation of serine residues in casein. Phosphorylation of serine residues was in keeping with the earlier demonstration by Lipmann and Levene* and Lipmann that the phosphate of the classical egg yolk and milk phosphoproteins, vitellinic acid or phosvitin, and casein, occurs principally in the form of phosphoserine. Later, Rabinowitz, and Lipmann detected and characterized a highly active phosphoprotein kinase in yeast. Our studies on histone phosphorylation grew out of work done in Lipmann’s laboratory on the isolation of a highly phosphorylated nonhistone nuclear protein fraction that acts as a substrate for liver phosphoprotein kinase.5 During further investigation of the phosphate content of various nuclear proteins, it was observed in our laboratory, and by others,B* that histone preparations contain small amounts of phosphoserine. These observations raised the possibility that histones are phosphorylated to a certain extent in cells, but evidence that the phosphoserine represents histone phosphorylation rather than contamination with highly phosphorylated nonhistone nuclear phosphoprotein was meager at that time. The interpretation that the phosphoserine found in histone preparations represents, at least in part, phosphorylated histone was favored by the findings that tissues contain a rather specific protein kinase which catalyzes the phosphorylation of histones and also of the functionally homologous basic proteins of certain fish sperm, the protamines. Also, at that time, Ingles and Dixon clearly demonstrated the phosphorylation of protamine in vivo in developing trout testis. More recently, a specific liver phosphatase for the dephosphorylation of histones and protamine has been characterized.1° The observation of Walsh and colleagues,ll made in collaboration with G. Dixon and B. Jergill, that preparations of skeletal muscle phosphorylase kinase kinase also catalyze a cyclic AMP-dependent phosphorylation of protamine prompted us to test the effect of cyclic AMP on liver histone kinase. Cyclic AMP was found to cause a marked stimulation of the histone kinase, but not the protamine kinase, activity of the liver enzyme preparations.12 Cyclic AMP-dependent histone kinase activity has since been shown to be widely distributed in tissues and organism^.*^-^^ In this paper, I will outline some of our studies on the phosphorylation

Thomas A. Langan

Papers

Histone Phosphorylation: Stimulation by Adenosine 3',5'-Monophosphate

Characterization of a Phosphatase Specific for Phosphorylated Histones and Protamine

Action of adenosine 3',5'-monophosphate-dependent histone kinase in vivo.

Cyclic amp and histone phosphorylation

Variation in Primary Structure at a Phosphorylation Site in Lysine-rich Histones