« AMINO ACID NEUROTRANSMITTER RECEPTORS Glutamate Receptors Glutamate receptors are found throughout the brain and are expressed on both neurons and glia ...» Document abstract
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SummaryGlutamate Receptors Glutamate receptors are found throughout the brain and are expressed on both neurons and glia, although not all glutamate receptor subtypes are found on both cell types. Glutamate receptors, sometimes referred to as excitatory amino acid receptors, were initially classified into N-methyl-D-aspartate (NMDA), quisqualate, and kainate receptors on the basis of their preferential activation by these exogenous agonists. More recently, five categories of glutamate receptors (NMDA, kainate, a-amino-3-hydroxy-5-methylisoxazole-4-propionic acid [AMPA], L-2-amino-4-phosphonobutyrate (L-AP4), and trans-1-aminocyclopentane-1,3-dicarboxylic acid [ACPD] receptors) have been established on the basis of pharmacological, electrophysiological, and molecular biological criteria. The L-AP4 receptor type is defined by its agonist and acts as an inhibitory autoreceptor, while the quisqualate receptors of the previous classification have been subdivided by means of more-specific agonists into AMPA and ACPD receptors. AMPA and Kainate receptors are sometimes collectively referred to as non-NMDA receptors. NMDA, kainate and AMPA receptors are ionotropic glutamate receptors; the L-AP4 and ACPD receptors are grouped as metabotropic receptors. Ionotropic receptors are ligand-gated cation-specific channels that are activated rapidly (milliseconds), whereas metabotropic receptors coupled to G proteins and second-messenger systems function more slowly on a scale of several hundred milliseconds to seconds.
Table of Contents- AMPA Receptors Recent cloning efforts have clearly demonstrated that AMPA and kainate receptors are distinct receptor complexes, although they can be activated by the same agonists.
- Kainate Receptors Although kainate is an effective agonist of AMPA receptors, it also activates its own distinct class of ionotropic receptors, the kainate-preferring receptors.
- NMDA receptors have a number of distinct recognition sites for endogenous and exogenous ligands, each with discrete binding domains. At present there are at least seven pharmacologically distinct sites through which compounds can alter the activity of this receptor.
- Metabotropic Receptors Not as much is known about the last group of glutamate receptors, the metabotropic receptors.
« neuromuscular junction, g-aminobutyric acid (GABA), and now exists about the primary structure of neurotransmitter receptors. has a large amino-terminal region ...» Document abstract
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biology
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SummaryClasses of Neurotransmitters Much of the information transfer between neurons in the CNS occurs via chemical synapses. These synapses use a variety of messengers (neurotransmitters) that are released in a Ca2+-dependent fashion from presynaptic terminals and act on specific protein receptors to produce biochemical and excitability changes in the receiving cell. There are two primary groups of neurotransmitters—low–molecular-weight amines and neuroactive peptides. These agents act on two classes of receptors, ligand-gated ion channels, at which the binding of the transmitter directly opens ion channels in the membrane, and G protein coupled receptors. The activated G protein then acts on ion channels or alters biochemical second-messenger systems. Physiologists classify synaptic transmission according to the speed of transmission (fast or slow) and according to the nature of the response (excitatory or inhibitory).
Table of Contents- Currently, there are nine low–molecular-weight amines that serve as neurotransmitters.
- Conductance Mechanisms Underlying Neurotransmitter Actions
- Structure of Neurotransmitter Receptors Considerable information now exists about the primary structure of neurotransmitter receptors.
- The ligand-gated ion channels gated by extracellular ATP (called P2X receptors) are exceptions to the scheme described above and have structures more typical of the inwardly rectifying K+ channels.
- G-protein coupled receptors have a distinctly different structure from the ligand-gated ion channels.
« Novel agonists at peptide receptors such as CRF or characterized in 1981 as a 41-amino acid peptide also functions as an extrahypothalamic neurotransmitter in ...» Document abstract
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SummaryNeuropeptide receptors have undergone the same process of discovery and characterization that receptors for other neurotransmitters have enjoyed. The process begins with the pharmacological characterization of the receptor's physicochemical binding properties by assessing the affinity of various metabolically derived and synthetic peptide fragments, and the native molecule, for the receptor binding site found in membrane preparations. Peptide receptor locations are mapped with radioactive or fluorescent tags that are inserted into peptide molecules, which often contain substituted amino acids at the most vulnerable peptidase cleavage sites. Previously, once the peptide receptor was characterized pharmacologically, it was usually purified from some relatively enriched biological tissue source or brain region by affinity column chromatography. After it had been purified, binding parameters and activity were recharacterized for the reconstituted purified receptor protein and structural information obtained by X-ray crystallography. This process was closely followed in the purification of the neurotensin-neuromedin N receptor.
Table of Contents- The neurotensin receptor was first characterized by photoaffinity labeling and cross-linking of radioiodinated ligands, which resulted in two labeled subunits of about 49 Kd and 51 Kd from rat brain synaptosomes.
- The much more powerful tools of molecular biology have been utilized more recently.
- Neuropeptide receptors have been associated with just about every type of second messenger signal transduction system that has been identified.
- Peptides are degraded to smaller fragments, and eventually to single amino acids, by specific enzymes termed peptidases.
- The metabolism of TRH has been investigated fairly completely, principally because of the limited number of fragments that can be generated from a tripeptide.
- The peptides involved in neuroendocrine regulation have cell bodies residing in the hypothalamus that receive feedback from all levels of the endocrine axes.
- Regional differences in CRF receptor regulation by corticosterone have also been reported, which have been shown to partly result from differential glycosylation of the CRF receptor.
- Alzheimer's Disease Dementia of the Alzheimer's Type represents up to two thirds of the demented population encountered in clinical practice, and over half of the nursing home beds in the United States are currently occupied by such patients.
- The CRF-containing interneurons of the cortex are also consistently depleted in Alzheimer's disease. As with SRIF, subcortical areas containing CRF neurons may be spared, but unlike SRIF, CRF receptors are increased in number (up-regulated) with no change in affinity.
- Corticotropin-Releasing Factor After a search spanning nearly three decades, CRF was isolated and characterized in 1981 as a 41-amino acid peptide.
- A series of studies have demonstrated significant elevations of CRF concentrations in the CSF of drug-free patients with major depression or following suicide.
- Like many other neuropeptide transmitters, central administration of SRIF produces a variety of behavioral and physiological effects.
- Decreased neurotensin concentrations in CSF have been reported in several populations of patients with schizophrenia when compared to controls or patients with other psychiatric disorders.
« within neurons from common amino acid precursors and within nerve terminals release neurotransmitter into the interact with postsynaptic receptors to alter the ...» Document abstract
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SummaryIn addition to similarities in neuronal organization, monoaminergic systems are similar with regard to their synthesis, storage, and degradation. Monoamines are synthesized within neurons from common amino acid precursors and taken up into synaptic vesicles via a vesicular monoamine transporter. Upon stimulation, vesicles within nerve terminals release neurotransmitter into the synaptic cleft. Once released, the monoamines interact with postsynaptic receptors to alter the excitability of postsynaptic cells. Monoamines may also interact with presynaptic autoreceptors located on the nerve terminal to suppress further release. In addition, released monoamines may be taken back up from the synaptic cleft into the nerve terminal by plasma membrane transporter proteins. Reuptake plays an important role in limiting the magnitude and duration of action of synaptically released monoamines. Once monoamines are taken up, they may be subject to enzymatic degradation or they may be protected from degradation by uptake into vesicles. The processing of acetylcholine differs from this scheme, and is described below.
Table of Contents- Serotonin The CNS contains less than 2 percent of the serotonin in the body; peripheral serotonin is located in platelets, mast cells, and enterochromaffin cells of the gastrointestinal system.
- The first step in the degradation of serotonin is mediated by monoamine oxidase (MAO) type A
- Two enzymes that play major roles in the degradation of catecholamines are monoamine oxidase and catechol O-methyltransferase
- Histamine As is the case for serotonin, the brain contains only a small portion of the histamine found in the body.
- Plasma Membrane Transporters A great deal of progress has been made in the molecular characterization of the monoamine plasma membrane transporter proteins.
- Vesicular Monoamine Transporter In addition to the reuptake of monoamines into the presynaptic nerve terminal, a second transport process serves to concentrate and store monoamines within synaptic vesicles.
« to their endocrine and neurotransmitter roles, many distribution of messenger ribonucleic acid (mRNA) for cleavage of specific amino acid sequences targeted by ...» Document abstract
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biology
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SummaryThe past several decades have witnessed a veritable explosion of knowledge about the central nervous system (CNS), and in no area has this been as impressive as in peptide neurobiology. Numerous peptide neurotransmitter candidates have been identified and characterized, their CNS distributions mapped, and their genes cloned. The tenet “one neuron-one transmitter” erroneously attributed to Dale has been convincingly refuted with numerous demonstrations of neurons containing multiple peptides or combinations of peptide and nonpeptide neurotransmitters. Additionally, since the early 1980s there has been an embarrassment of riches in the form of knowledge about neurotransmitter receptor diversity, diversity of receptor-effector coupling, and neurotransmitter transporters. These discoveries have not yet been fully integrated into what is known about normal or aberrant CNS function, although dysfunction at virtually any level could conceivably lead to neuropsychiatric deficits.
Table of Contents- By definition, a neuropeptide is a chain of two or more amino acids linked by peptide bonds, and differs from other proteins only in the length of the amino acid chain.
- Many of the known behavioral effects of neuropeptides are observed only after their direct injection into the CNS because most peptides do not penetrate the blood-brain barrier in amounts sufficient to produce effects before being inactivated by serum and tissue enzymes that degrade them.
- The tertiary structure for recognition is also used by the immune system for the production of specific antibodies, as well as by biological receptors.
- Neuropeptides are found throughout the CNS, as well as in various peripheral organs, such as the gastrointestinal tract, pancreas, and adrenal glands.
- In the cortex of rats SRIF is found in some of the large stellate-shaped neurons and in abundance among the fusiform-shaped, nonpyramidal neurons of layers II to V, and particularly in layer V of the sensory cortex.
- Through the use of retrograde tracing methods and dual staining techniques, several pathways for certain peptides have now been delineated.
- Some of the noradrenergic locus ceruleus neurons, in turn, project to the hypothalamic paraventricular nucleus where their input increases CRF synthesis and release.
- The neurotensin-neuromedin N gene was originally cloned from canine ileal mucosa, and complementary deoxyribonucleic acid (cDNA) probes constructed against this form were used to clone the rat gene.
« NMDA antagonists, ketamine (Ketalar) and D-amino-propyl-valeric acid, have consistently GABA, as the major inhibitory neurotransmitter in the CNS, can be ...» Document abstract
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SummaryGABAA Receptor The GABAA receptor is a member of the superfamily of ligand-activated ion channels in the cell membrane. GABA type A (GABAA) receptors are most closely related to strychnine-sensitive glycine receptors, more distantly related to acetylcholine nicotonic receptors and serotonin 5-hydroxytryptamine (5-HT) [5-HT] type receptors, and even more distantly related to glutamate ionotropic receptors (AMPA and kainate receptors and NMDA receptors). GABAA receptors are heteropentameric protein complexes, which when activated undergo a series of conformational changes that form an open channel (pore) selectively permeable to anions, specifically chlorine anion (Cl–) and to a lesser degree (HCO–3). Receptor activation normally results in an influx of Cl– which rapidly and transiently hyperpolarizes the membrane, a process generally referred to as the generation of an inhibitory postsynaptic potential. The increase in Cl– flux also decreases the resistance of the membrane, which acts as a shunt to impede the ability of depolarizing excitatory postsynaptic potentials to elicit action potentials (nerve impulses).
Table of Contents- GABAA receptors are heteromeric in that the receptor can comprise at least four types of subunit proteins, termed a, b, g, and d. It is pentameric in that each receptor has a total of five proteins
- A variety of pharmacological agents can influence the activity of GABAA receptors
- GABAB Receptors The metabotropic GABAB receptors are a member of the superfamily of G-protein-coupled receptors expressed in the cell membrane.
- However, it is likely that a breakdown in the regulation of glutamate is a major factor.
- Epilepsy Epilepsy is a group of neurological disorders characterized by spontaneous recurrent seizures.
- Although many neurobiological factors may contribute to seizure formation, a prominent feature of most seizures is an abnormal and excessive firing of glutamatergic neural pathways.
- Kindling, which is a gradual induction of a hyperexcitable neuronal state, can occur by focal repetitive subconvulsive stimulation of the hippocampus, amygdala, or some other brain areas.
- Neuropathic Pain Activation of afferent C fibers with nociceptive stimuli produces pain sensations that are enhanced during pathological conditions.
- A pregnane-derived synthetic neurosteroid is in clinical trials for treatment of epilepsy.
- Substance Abuse Ethanol enhances GABA receptor function in some in vitro preparations potentially via a protein-binding site.
« been examined using mutations of specific amino acid residues. but are blocked by the neurotransmitter, acetylcholine, acting at muscarinic receptors. . ...» Document abstract
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SummaryStructure and Function of Voltage-Gated Ion Channels Voltage-gated ion channels allow the flow of ions in response to changes in membrane voltage and are key elements in neuronal excitation and inhibition. Although ion channels can usually pass more than a single type of ion, voltage-gated channels are named according to the predominant ion that flows when the channel is open. Ion channels that are selective for Na+, K+, Ca2+, or Cl– have been described in neuronal membranes. Certain ion channels that are gated directly by chemical neurotransmitters such as glutamate and acetylcholine are selective for Na+, K+, and Ca2+ but exclude Cl– and are called nonselective cationic channels.
Table of Contents- Sodium (Na+) Channels Na+ channels are primarily responsible for the fast upstroke of action potentials, although in some neurons Na+ channels also contribute to lower-level depolarizations and pacemaker firing.
- Relations between primary protein structure and ion channel function in Na+ channels have been examined using mutations of specific amino acid residues.
- The net effect is similar to the scorpion toxins. Finally, certain local anesthetic drugs, including lidocaine and procaine, block Na+ channels by binding reversibly to sites within the hydrophobic regions of the ion channel.
- Delayed-rectifier channels open slowly and show little inactivation during prolonged depolarizations.
- M channels represent a class of K+ channels that are activated in a time- and voltage-dependent fashion but are blocked by the neurotransmitter, acetylcholine, acting at muscarinic receptors.
- KATP channels exist in the CNS and appear to be involved in regulating the release of certain neurotransmitters and perhaps in determining the response of some neurons to changes in intracellular energy levels.
- Calcium (Ca2+) Channels Because Ca2+ is involved in numerous cellular events including enzyme activation, gene expression, and neurotransmitter release, the regulation of intracellular Ca2+ levels is of major importance to neurons.
- Most structural information about Ca2+ channels comes from skeletal muscle HVA Ca2+ channels.
« where they act to reduce neurotransmitter release Conversely, hallucinogens such as lysergic acid diethylamide (LSD differ in length by 29 amino acids, products ...» Document abstract
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SummaryUltimately the effects of monoamines on CNS function and behavior depend upon their interactions with receptor molecules. The binding of monoamines to these plasma membrane proteins initiates a series of intracellular events that modulate neuronal excitability. Unlike the transporters, multiple receptor subtypes exist for each monoamine transmitter. The initial classification of many receptor subtypes was based on radioligand binding studies. Receptor binding sites were identified on the basis of the rank order of binding affinities for a number of agonist and antagonist compounds. More recently, the molecular cloning of monoamine receptors has confirmed that many of the sites initially defined by these binding studies did indeed correspond to distinct receptor proteins encoded by unique genes. Molecular cloning has also led to the identification of previously unknown receptors, and to the introduction of powerful tools to characterize receptor structure and function.
Table of Contents- Neurotransmitter receptors produce intracellular effects by one of two basic mechanisms:
- In the wake of the recent proliferation of known receptors subtypes, much work needs to be done to determine the functional roles of individual receptors.
- The 5-HT1 receptors comprise the largest serotonin receptor subfamily, with human subtypes designated:
- At least three receptor subtypes mediate the effects previously attributed to a single 5HT2 receptor subtype.
- The 5-HT3 receptor is unique among monoaminergic receptors in its membership within the ligand-gated ion channel superfamily.
- The D1 receptor was initially distinguished from the D2 subtype by its high affinity for the antagonist SCH 23390 and its relatively low affinity for butyrophenones such as haloperidol
- The dopamine D2 receptor was initially distinguished from the D1 receptor on the basis of its high affinity for butyrophenones.
- The D3 and D4 receptors are considered to be D2-like on the basis of similarities in their gene structures, sequence homologies, and pharmacology.
- Like the a-adrenergic receptors described, b-adrenergic receptors (designated including subtypes b1, b2, and b3) are found both in the brain and in many peripheral tissues.
- Unlike H1 and H2 histamine receptors, H3 receptors are located presynaptically on axon terminals.
- Within the human brain, nicotinic acetylcholine receptors are found at highest densities within the hippocampal formation, neocortex, substantia nigra, ventral tegmental area, dorsal raphe nucleus, periaqueductal gray, and the basal forebrain cholinergic complex.
« The binding of neurotransmitter to their receptors N-Methyl-D-aspartate glutamate receptors, that permit is phosphorylated on a critical amino acid (Ser133) by ...» Document abstract
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SummaryAs a first approximation, genes can be defined as stretches of DNA that encode a single protein or a single functional RNA, such as an rRNA or tRNA. There are exceptions to this rule because there are mechanisms, such as alternative splicing of the primary RNA transcript into different mRNAs, that may intervene between a given gene and a finished protein. As a result, in some cases a single gene may actually encode multiple proteins.
Table of Contents- The chromosomes of eukaryotic cells are so long that they would not fit in the nucleus in their extended form.
- Proteins are not synthesized directly from the DNA that encodes them, but in two sequential processes
- Many genes contain multiple introns and exons that may not be spliced identically in every cell type or in a given cell type at every stage of development.
- Regulatory sequences within DNA control the expression of genes by virtue of their ability to bind specific regulatory proteins.
- Those cis-regulatory elements that specify the site within a gene at which transcription starts, and upon which the complex of proteins that forms the basal transcription apparatus is assembled, are called the basal or core promoter.
- Transcription factors that are tethered to DNA by binding cis-elements often have a modular structure comprised of physically separate domains
- Environmental stimuli are transduced by neurons into neurotransmitter signals.
- CRE binding protein (CREB) is the major protein that binds cAMP response element in most cell types that have been investigated.
- The convergence of multiple signaling pathways (the cAMP and Ca2+ pathways) on a single transcription factor has important implications.
- CREB has also shown to be phosphorylated in the striatum, including the nucleus accumbens, in response to the administration of cocaine and amphetamine, and to be activated in the locus nucleus coeruleus during opiate withdrawal.
- The AP-1 proteins generally bind DNA as heterodimers comprised of one member each of two different families of related proteins, the Fos family and the Jun family.
- IEG mapping is now one of the fundamental tools of functional neuroanatomy.
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