Second messengers in the regulation of nerve cell plasticity during learning

A review of 1972 to 1988 publications is presented, as well the data obtained by the authors on the influence of second messengers and their intracellular receptors on neuron plasticity in the learning experimental models. The emphasis is laid on cyclic 3',5'-adenosine monophosphate; cyclic 3',5'-guanosine monophosphate, calcium ions and their intracellular receptor calmodulin, as well as on the metabolites of phosphoinositide exchange: inositol-1, 4, 5-trisphosphate, 1,2-diacylglycerol and protein kinase C activated by the latter and arachidonic acid.     

The role of lipid second messengers in aldosterone synthesis and secretion

Second messengers are small rapidly diffusing molecules or ions that relay signals between receptors and effector proteins to produce a physiological effect. Lipid messengers constitute one of the four major classes of second messengers. The hydrolysis of two main classes of lipids, glycerophospholipids and sphingolipids, generate parallel profiles of lipid second messengers: phosphatidic acid (PA), diacylglycerol (DAG), and lysophosphatidic acid versus ceramide, ceramide-1-phosphate, sphingosine, and sphingosine-1-phosphate, respectively. In this review, we examine the mechanisms by which these lipid second messengers modulate aldosterone production at multiple levels. Aldosterone is a mineralocorticoid hormone responsible for maintaining fluid volume, electrolyte balance, and blood pressure homeostasis. Primary aldosteronism is a frequent endocrine cause of secondary hypertension. A thorough understanding of the signaling events regulating aldosterone biosynthesis may lead to the identification of novel therapeutic targets. The cumulative evidence in this literature emphasizes the critical roles of PA, DAG, and sphingolipid metabolites in aldosterone synthesis and secretion. However, it also highlights the gaps in our knowledge, such as the preference for phospholipase D-generated PA or DAG, as well as the need for further investigation to elucidate the precise mechanisms by which these lipid second messengers regulate optimal aldosterone production.     

Lipoxygenase inhibitors, eicosapolynoic acids, attenuate the short-term plasticity of the cholinoreceptors of snail neurons]

On identified Helix neurones RPa3 and LPa3 with the use of the double-electrode voltage clamp technique on the membrane the influence was studied of three polyacetilenic analogues of natural polyenoic acids which were the inhibitors of their lipoxygenase oxidation on the dynamics of inward current extinction, caused by the repeated iontophoretic applications of acetylcholine to soma. It was found that 5, 8, 11, 14-eicosatetraynoic acid (30-60 microM) and 5, 8, 11, 14, 17-eicosapentaynoic acid (4-5 microM) decreased the amplitude of inward current caused by acetylcholine leading and weakened its extinction at the repeated applications. The third analogue -8, 11, 14-eicosatrynoic acid had no modulating influence on the value of current and on its extinction. The supposition was made that lipoxygenase metabolites of polyenoic acids regulated plasticity of Helix neurones cholinoreceptors. Considering different inhibiting by the used compounds of various lipoxygenases the most probable was participation in regulation of cholinoreceptors plasticity of those eicosanoids which were formed from arachidonic acid under the influence of 5-lipoxygenase. Regulating role of eicosanoids formed at the action of other lipoxygenases was not excluded.     

Synaptic lipid signaling: significance of polyunsaturated fatty acids and platelet-activating factor

Neuronal cellular and intracellular membranes are rich in specialized phospholipids that are reservoirs of lipid messengers released by specific phospholipases and stimulated by neurotransmitters, neurotrophic factors, cytokines, membrane depolarization, ion channel activation, etc. Secretory phospholipases A2 may be both intercellular messengers and generators of lipid messengers. The highly networked nervous system includes cells (e.g., astrocytes, oligodendrocytes, microglial cells, endothelial microvascular cells) that extensively interact with neurons; several lipid messengers participate in these interactions. This review highlights modulation of postsynaptic membrane excitability and long-term synaptic plasticity by cyclooxygenase-2-generated prostaglandin E2, arachidonoyldiacylcylglycerol, and arachidonic acid-containing endocannabinoids. The peroxidation of docosahexaenoic acid (DHA), a critical component of excitable membranes in brain and retina, is promoted by oxidative stress. DHA is also the precursor of enzyme-derived, neuroprotective docosanoids. The phospholipid platelet-activating factor is a retrograde messenger of long-term potentiation, a modulator of glutamate release, and an upregulator of memory formation. Lipid messengers modulate signaling cascades and contribute to cellular differentiation, function, protection, and repair in the nervous system. Lipidomic neurobiology will advance our knowledge of the brain, spinal cord, retina, and peripheral nerve function and diseases that affect them, and new discoveries on networks of signaling in health and disease will likely lead to novel therapeutic interventions.     

Minireview: Functional Modulation of Ligand-Gated GABAA and NMDA Receptor Channels by Phosphorylation

Abstract

Ion channels are ubiquitous membrane proteins that may be organized into different families according to their predicted transmembrane topology. They are concerned with rapid signalling over plasma and intracellular membranes and are activated, depending on their type, by transmembrane voltage, intracellular second messengers or extracellular neurotransmitters. Intracellular activities of protein kinases and phosphatases act to modulate ion channel activity (e.g. ref. 1). The modulation of the function of ligand activated, neuronal ion channels, that are crucial for synaptic transmission, may be an important basis for a modulation of a synaptic efficiency. The following review concentrates, due to space limitations, on the postranslational modification, and on the modulation of the function by protein kinase C and protein kinase A, of ligand-gated GABA_A channels and NMDA channels on a molecular level.     

Use 'em and lose 'em-activity-induced removal of calcium channels from the plasma membrane

Calcium influx via L-type (Cav1.2 and Cav1.3) calcium channels is tightly regulated to ensure optimal intracellular calcium levels. Although much is known about acute modulation of these channels by second messengers, the mechanisms that control their trafficking to and from the plasma membrane remain poorly understood. In this issue of Neuron, Green and colleagues demonstrate that the opening of L-type calcium channels results in negative feedback regulation due to their calcium-dependent internalization.     

Glucose metabolism, second messengers and insulin secretion

Insulin secretion from beta cells of the islets of Langerhans in the endocrine pancreas is regulated by glucose, glucose metabolites, metabolic intermediates such as ATP, acetyl CoA and reduced pyridine nucleotides, and classical second messengers. Receptor responses transduced by guanine nucleotide binding proteins modulate metabolic activity, the generation of second messengers, and cell depolarization during stimulus-response coupling in the beta cell. This review will consider insulin secretion as regulated by glucose metabolic pathways and second messengers.     

Formation of NO and H2O2 in endometrial stromal cells under the effect of acetylcholine

While conducting the experimental work the possibility both the basal and activated by acetylcholine NO and H2O2 production by uterus endometrium stromal cells was estimated. The results obtained give a ground to suppose the existence of two types of cholinoreceptors in the tesyed cells via which two signal transduction ways are fulfilled. The concentrational and temporal dependancy of these metabolites synthesis have a cyclic character. The hypothesis is revealed about a principal possibility of NO and N2O2 to come forward in the role of secondary messengers of the endometrium stromal cells as well as prrovide for the paracrine regulation of myometrium functioning.     

Status epilepticus--the new mechanisms and lines of inhibition (the lithium-pilocarpine model)

This review focuses on the modeling of status epilepticus in animal brain and modern data on the mechanisms of epileptical seizures initiation using the pilocarpine binding with the muscarinic cholinoreceptors (litium pilocarpine model). The character of epileptics seizures in developing brain and adult brain of rats were investigated. The lines of modulation and inhibition epileptics statues by sacricine and intranasal application of neuropeptide thyroliberin in ultra-low doses are demonstrated. The role of the short-term changes (signal regulated kinase signaling cascade, Kv 4.2 potassium channels, hippocampal and cortical spike-wave discharges) and the long-term changes (loss of selective type of interneurons, excitatory circuits by mossy fiber sprouting) that promotion the epileptic state and recurrent seizures in limbic structure are discussed.     

Overview of Voltage-Dependent Calcium Channels

Voltage-dependent calcium channels couple electrical signals to cellular responses in excitable cells. Calcium channels are crucial for excitation–secretion coupling in neurons and endocrine cells, and excitation–contraction coupling in muscle. Several pharmacologically and kinetically distinct calcium channel types have been identified at the electrophysiological and molecular levels. This review summarizes the basic properties of voltage-dependent calcium channels, including mechanisms of ion permeation and block, gating kinetics, and modulation by G proteins and second messengers.     

Calcium regulation of the short-term plasticity of the cholinoreceptors in neurons RPa3 and LPa3 of the edible snail]

Pharmacological influences, changing intracellular content of Ca2+, reversibly change the speed and depth of extinction of the input current of the Helix RPa3 and LPa3 neurones, elicited by a repeated iontophoretic application of acetylcholine to the soma. Suppression by extracellular medium, devoid of Ca2+ and by verapamyl (100-150 mumol/l) of Ca2+ input to the cell, induced by cholinoreceptors activation, reversibly weakens the extinction. Raise of intracellular Ca2+ level by blockade with ruthenium red (5-10 mumol/l) of specific Ca2+ transport by mitochondria and by mobilization with caffeine (1-4 mmol/l) of Ca2+, deposited by endoplasmic reticulum, accelerates and intensifies the extinction. The obtained results testify that the short-term cholinoreceptors plasticity of the above neurones is positively controlled by Ca2+ entering the cell by chemically controlled ion channels and mobilized from intracellular Ca-depot.     

Role of protein kinase C in cellular regulation

Protein kinase C (PKC) consists of a family of closely related enzymes ubiquitously present in animal tissues. These enzymes respond to second messengers, Ca2+, diacylglycerol and arachidonic acid, to express their activities at membrane locations. Numerous hormones, neurotransmitters, growth factors and antigens are believed to transmit their signals by activation of a variety of phospholipases to generate these messengers. The various PKC isozymes, which exhibit distinct biochemical characteristics and unique cellular and subcellular localizations, may be differentially stimulated depending on the duration and strength of these messengers. Activation of PKC has been linked to the regulation of cell surface receptors, ion channels, secretion, gene expression, and neuronal plasticity and toxicity. The mechanisms of action of PKC in the regulation of these cellular functions are not entirely clear. Further study to identify the target substrates relevant to the various cellular functions is essential to define the functional diversity of this enzyme family.     

Architecture of physiological functions: the same basis but new aspects

The principles of physiological functions formulated by J. Barckroft (constancy of the internal medium, reserves, any adaptation as an integration, principle of antagonism, doubling of mechanisms) are compared with principles of modern physiology. The place and role of physiology in the life sciences are discussed. The necessity of taking into consideration 4 level of regulation of functions (the nervous system, hormones, autacoids, physicochemical factors of the extracellular fluid) is substantiated, as well as the necessity of identification of 4 levels of organization of physiological systems. The main role of the water-salt homeostasis in maintaining the cell volume is suggested. Significance of various types of receptors and second messengers in regulation and modulation of functions is shown.     

Regulation of neuron cholinoreceptor plasticity of Helix lucorum by second messengers and opioids

The rhythmical local ionophoretic applications of acetylcholine (ACh) to the somatic membrane of Helix lucorum identified neurons evokes the reversible depression of the ACh-induced response which shows cholinoreceptor (ChR) desensitization. ChR desensitization is regulated not by one but by several known second messengers and G-proteins. The endogenous opioids perform the excitation or inhibitory tonic control of the membrane potential in some neurons constantly activating the ionotropic opiate receptors. The direction of neuron ChR desensitization modulation by opioids depends on the type of the activated modulatory opiate receptors (mu or kappa) on the neuron membrane. Second messengers are involved in intracellular mechanism of modulation of the ChR desensitization by opiate kappa-agonist bremazocine.     

Endocytosis of the vasopressin receptor by anterior pituitary cells is increased by corticotropin-releasing factor (CRF)

Endocytosis of certain receptors such as the transferrin receptor and the EGF-receptor appears to be influenced by second messengers. If second messengers are involved in modulation of endocytosis, not only endocytosis of the stimulated receptor itself but also of receptors for other ligands on the cell surface may be influenced by receptor occupancy. Corticotropin-releasing factor (CRF) and vasopressin act synergistically on secretion of ACTH from the anterior pituitary. The results presented here demonstrate that CRF increases retrieval of the vasopressin receptor in anterior pituitary cells in primary culture without influencing the surface binding of vasopressin. This is not a function of an increased membrane turnover since endocytosis of the transferrin receptor is not influenced by CRF.     

Differences in the habituation of the nicotinic and muscarinic cholinoreceptors of Helix neuron PPa4

Pharmacological division of the snail cholinoreceptors population of the identified neurone RPa4 by cholinoblockators of muscarine (atropine, platyphylline) and nicotine (d-tubocurarine) receptors allowed to reveal differences in the dynamics of reversible reduction of sensitivity of these receptors during their habituation to repeated iontophoretic acetylcholine applications. Maximum desensitization of nicotine receptors is weaker, develops slower and is eliminated faster after the end of rhythmic acetylcholine applications. An assumption is made that a more rapid and deeper lowering of muscarine cholinoreceptors sensitivity is due to an increase of intracellular concentration of free calcium at their activation by the agonist.     

Calcium ion modulation of short-term plasticity of the cholinoreceptor membrane of the mollusk neuron

Repeated iontophoretic acetylcholine applications to the external surface of the plasma membrane of identified Helix neurones elicit a gradual reversible reduction of cholinoreceptors (ChR) sensitivity. Influence on Ca-conductivity of neuronal membrane modifies the dynamics of lowering of ChR sensitivity. Administration of cadmium ions--blockader of Ca-conductivity, slows down and weakens ChR habituation, while Ca-conductivity activation by raising of extracellular Ca2+ content accelerates and deepens the habituation. It is suggested that chemo-controlled Ca-conductivity takes part in regulation of short-term ChR plasticity.     

Signal-transduction pathways that regulate smooth muscle function. II. Receptor-ion channel coupling mechanisms in gastrointestinal smooth muscle

Regulation of membrane ion channels by second messengers is an important mechanism by which gastrointestinal smooth muscle excitability is controlled. Receptor-mediated phosphorylation of Ca(2+) channels has been known for some time; however, recent findings indicate that these channels may also modulate intracellular signaling. The plasmalemma ion channels may also function as a point of convergence between different receptor types. In this review, the molecular mechanisms that link channel function and signal transduction are discussed. Emerging evidence also indicates altered second-messenger modulation of the Ca(2+) channel in the pathophysiology of smooth muscle dysmotility.     

Sea urchin sperm cation-selective channels directly modulated by cAMP

Components of the sea urchin outer egg jelly layer such as speract drastically change second messenger levels and membrane permeability in sperm. Ion channels are deeply involved in the sperm-egg dialogue in sea urchin and other species. Yet, due to the small size of sperm, studies of ion channels and their modulation by second messengers in sperm are scarce. In this report we offer the first direct evidence that cation-selective channels upwardly regulated by cAMP operate in sea urchin sperm. Due to their poor selectivity among monovalent cations, channel activation in seawater could contribute to sperm membrane repolarization during the speract response.