Showing papers by "Michael W. Salter published in 1999"
TL;DR: It is proposed that the boost in NMDA receptor function produced by the coincidence of activating Src and raising intracellular sodium may be important in physiological and pathophysiological enhancement of excitatory transmission in the dorsal horn of the spinal cord and elsewhere in the central nervous system.
Abstract: The N-methyl-d-aspartate (NMDA) receptor is a principal subtype of glutamate receptor mediating fast excitatory transmission at synapses in the dorsal horn of the spinal cord and other regions of the central nervous system. NMDA receptors are crucial for the lasting enhancement of synaptic transmission that occurs both physiologically and in pathological conditions such as chronic pain. Over the past several years, evidence has accumulated indicating that the activity of NMDA receptors is regulated by the protein tyrosine kinase, Src. Recently it has been discovered that, by means of up-regulating NMDA receptor function, activation of Src mediates the induction of the lasting enhancement of excitatory transmission known as long-term potentiation in the CA1 region of the hippocampus. Also, Src has been found to amplify the up-regulation of NMDA receptor function that is produced by raising the intracellular concentration of sodium. Sodium concentration increases in neuronal dendrites during high levels of firing activity, which is precisely when Src becomes activated. Therefore, we propose that the boost in NMDA receptor function produced by the coincidence of activating Src and raising intracellular sodium may be important in physiological and pathophysiological enhancement of excitatory transmission in the dorsal horn of the spinal cord and elsewhere in the central nervous system.
131 citations
TL;DR: It is concluded that Src-induced potentiation of NMDAR currents is not mediated by reducing Zn2+ inhibition in hippocampal and dorsal horn neurons.
Abstract: The protein-tyrosine kinase Src is known to potentiate the function of NMDA receptors, which is necessary for the induction of long-term potentiation in the hippocampus. With recombinant receptors composed of NR1-1a/NR2A or NR1-1a/2B subunits, Src reduces voltage-independent inhibition by the divalent cation Zn2+. Thereby the function of recombinant NMDA receptors is potentiated by Src only when the Zn2+ level is sufficient to cause tonic inhibition. Here we investigated whether the Src-induced potentiation of NMDA receptor function in neurons is caused by reducing voltage-independent Zn2+ inhibition. Whereas chelating extracellular Zn2+ blocked the Src-induced potentiation of NR1-1a/2A receptors, we found that Zn2+ chelation did not affect the potentiation of NMDA receptor (NMDAR) currents by Src applied into hippocampal CA1 or CA3 neurons. Moreover, Src did not alter the Zn2+ concentration-inhibition relationship for NMDAR currents in CA1 or CA3 neurons. Also, chelating extracellular Zn2+ did not prevent the upregulation of NMDA single-channel activity by endogenous Src in membrane patches from spinal dorsal horn neurons. Taking these results together we conclude that Src-induced potentiation of NMDAR currents is not mediated by reducing Zn2+ inhibition in hippocampal and dorsal horn neurons.
64 citations
TL;DR: Jo and Schlichter describe GABA and ATP corelease from the same presynaptic cell, which suggests that a dorsal horn synapse could be excitatory or inhibitory depending on its postsynaptic receptors or the amount of transmitter released.
Abstract: Jo and Schlichter describe GABA and ATP corelease from the same presynaptic cell, which suggests that a dorsal horn synapse could be excitatory or inhibitory depending on its postsynaptic receptors or the amount of transmitter released.
11 citations
TL;DR: The chapter demonstrates that spinal cord astrocytes express two functionally distinct subtypes of nucleotide receptor, and reveals that the differing Ca 2+ signals evoked by the different receptors may have distinct functional consequences in terms of signal discrimination, gene expression, growth, and proliferation.
Abstract: Publisher Summary The chapter focuses on the characterization of Ca 2+ signals evoked by extracellular purine and pyrimidine nucleotides in astrocytes from the spinal cord. The chapter demonstrates that spinal cord astrocytes express two functionally distinct subtypes of nucleotide receptor. One receptor appears to be the cloned P2Y 1 receptor while the other represents a novel P2Y receptor subtype activated by uridine- 5 '-triphosphate (UTP). Each receptor couples to the release of Ca 2+ from IP 3 -sensitive intracellular stores but when subjected to sustained stimulation the two subtypes of receptor induce distinctive Ca 2+ response patterns. The chapter reveals that the differing Ca 2+ signals evoked by the different receptors may have distinct functional consequences in terms of signal discrimination, gene expression, growth, and proliferation. The morphological changes induced by ATP stimulation of astrocytes require prolonged periods of stimulation. Thus, in terms of possible involvement of the two metabotropic P2 receptors, involvement of the P2Y receptor seems unlikely as the Ca 2+ signal evoked by stimulating this receptor subtype fades rapidly with sustained stimulation. On the other hand, the pyrimidinoceptor-triggered Ca 2+ signal persists during the prolonged elevations of extracellular nucleotide.
5 citations
TL;DR: Recent evidence indicates that, in addition to being the principal charge carrier for action potentials, once inside neurons sodium functions as an intracellular second messenger by upregulating the activity of NMDA receptors.
Abstract: Recent evidence indicates that, in addition to being the principal charge carrier for action potentials, once inside neurons sodium functions as an intracellular second messenger by upregulating the activity of NMDA receptors.
3 citations
TL;DR: Using the reagents described in the chapter in recordings from terminals of mammalian central synapses it is now possible to determine whether there are presynaptic effects of Src and thus to gain a comprehensive understanding of the diverse roles of this kinase in synaptic transmission in the CNS.
Abstract: Publisher Summary This chapter discusses the application of recombinant proteins, peptides and antibodies in exploring the role of Src in regulating synaptic function. Recombinant proteins, peptides and antibodies provide useful tools for examining the role of intracellular signaling proteins in synaptic function in the CNS. Such tools helps in identifying Src as an endogenous PTK which enhances the function of NMDA channels in CNS neurons and determines that activating Src is necessary for the induction of LTP in the CA1 region of the hippocampus. These observations highlight the importance of investigating physiological processes in wild-type animals when appropriately selective reagents are available. The chapter focuses on postsynaptic roles for Src in regulating synaptic transmission but Src is also found presynaptically and it is known that voltage-gated K + and Ca 2 + channels are regulated by Src kinases. Using the reagents described in the chapter in recordings from terminals of mammalian central synapses it is now possible to determine whether there are presynaptic effects of Src and thus to gain a comprehensive understanding of the diverse roles of this kinase in synaptic transmission in the CNS.