Cell to Cell: December 2006

cellular signalling

Cells, whether unicellular organisms or cells within multicellular organisms, respond to signals within their environment. Such signals include mechanical stimuli (light, sound) and chemicals. The origin of chemical stimuli may be the cell itself (autocrine), adjacent cells (paracrine), the plasma membrane of adjacent cells (contact inhibition), or distant cells (endocrine). Cytokines mediate paracrine stimulation, and hormones mediate endocrine stimulation.

Cellular responses to signalling molecules include alterations in gene expression (transcription), alteration of electrophysiological charge, and alteration of metabolic activity of the cell.

neurotransmission

Roughly 10 small-molecule transmitters and over 50 recognized neuroactive peptides comprise the commonly recognized neurotransmitters, molecules involved in signalling between cells. A variety of macromolecules act as receptors for neurotransmitters and hormones (molecules that act at a distance from their production).

There exist numerous receptors for each neurotransmitter, so receptors play an important role in neurotransmission. Most neurotransmitter receptors belong to a class of proteins known as the serpentine receptors, or GPCRs, in which a characteristic trans-membrane structure spans the cell membrane seven times. Intracellular signalling is carried out by association of the neurotransmitter with G-proteins (small GTP-binding and hydrolyzing proteins), or with protein kinases, or by the receptor itself in the form of a ligand-gated ion channel (acetylcholine receptor). Neurotransmitter receptors are subject to ligand-induced desensitization whereby they become unresponsive upon prolonged exposure to their neurotransmitter. The NMDA receptor is a neural receptor that is expressed at excitatory glutamatergic synapses and is critical for normal brain function. At a cellular level, this receptor plays a pivotal role in triggering and controlling synaptic plasticity, and so is important for learning and memory.

Among the small-molecule neurotransmitters are: acetylcholine, 5 amines, and 3 or 4 amino acids. The purines adenosine, ATP, GTP, and their derivatives are also neurotransmitters. In addition to amines, amino acids, purines, and acetylcholine, fatty acids are candidates for neurotransmitter (endogenous canabinoid). The monoamine neurotransmitters include the catecholamines dopamine, epinephrine, and norepinephrine, which are derived from the amino acids phenylalanine and tyrosine. Serotonin, or 5-HT is a monoamine product of the amino acid tryptophan. The hydrophilic vasoactive amine histamine is derived from the amino acid histidine. Aspartate, glutamate, and GABA are also derived from amino acids (aspartic acid, glutamic acid). Glycine is the smallest amino acid, and acts as a neurotransmitter.

The catecholamine neurotransmitter dopamine is a precursor in the biosynthetic pathway to the other catecholamine neurotransmitters epinephrine (adrenaline) and norepinephrine (noradrenaline). Dopamine is synthesized in the body (predominantly in neurons and adrenals) by the decarboxylation of l-dopa by the enzyme aromatic-L-amino-acid decarboxylase. Dopamine beta hydroxylase converts dopamine to norepinephrine, and phenylethanoamine N-methyl transferase converts norepinephrine to epinephrine.

GPCRs

Guanine nucleotide-binding protein-coupled receptors, also termed serpentine receptors, transduce signals from transmembrane receptors for sensory, hormonal, or photic stimuli into regulation of effector enzymes and ion channels. GPCRs are diverse and of ancient evolutionary lineage, and are found in fungi, plants, and animals. They share a common structure of plasma membrane-spanning helices with seven hydrophobic domains (7-TMSs). GPCRs are typically 20-28 amino acid residues long.

GPCRs are trimeric proteins that respond to a variety of specific ligands and stimuli – for example, photons, ions, biogenic amines, nucleosides, lipids, amino acids, and peptides. Transmembrane GPCRs bind GDP when inactive, and switch the bound nucleotide to GTP when activated.

The signalling cascade begins with attachment of a specific neurotransmitter ligand or a specific energetic stimulus, which initiates brief (seconds) binding of GTP rather than GDP. Signal transduction is accomplished through the coupling of G proteins to various secondary pathways involving ion channels, adenylyl cyclases, and phospholipases. Further, GPCRs may also couple to other proteins, such as those containing PDZ domains.

It is anticipated that future elucidation of GPCR constitution will reveal alpha-helical structures, consisting of 20 to 28 amino acids each.

On-line structural representations for the human µ opioid receptor, for example, is available as a 2D schematic. The 3D structure for inactive (dark) rhodopsin has been established, and the GPCRDB server holds atomic coordinates of 3D models of GPCRs. For more detailed information on-line about GPCRs, consult the GPCR database at GPCRDB.

The GPCRs have been divided into at least six families of GPCRs showing little to no sequence similarity.

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GPCR families

The GPCRs have been divided into at least six families of GPCRs showing little to no sequence similarity:

Class A Rhodopsin like: Amine, Peptide, Hormone protein, (Rhod)opsin, Olfactory, Prostanoid, Nucleotide-like, Cannabinoid, Platelet activating factor, Gonadotropin-releasing hormone, Thyrotropin-releasing hormone & Secretagogue, Melatonin, Viral, Lysosphingolipid & LPA (EDG), Leukotriene B4 receptor, Class A Orphan/other.

Class B Secretin like: Calcitonin, Corticotropin releasing factor, Gastric inhibitory peptide, Glucagon, Growth hormone-releasing hormone, Parathyroid hormone, PACAP, Secretin, Vasoactive intestinal polypeptide, Diuretic hormone, EMR1, Latrophilin, Brain-specific angiogenesis inhibitor (BAI), Methuselah-like proteins (MTH), Cadherin EGF LAG (CELSR).

Class C Metabotropic glutamate / pheromone: Metabotropic glutamate, Calcium-sensing like, Putative pheromone receptors, GABA-B, Orphan GPCR5, Orphan GPCR6, Bride of sevenless proteins (BOSS), Taste receptors (T1R).

Class D Fungal pheromone: Fungal pheromone A-Factor like (STE2,STE3), Fungal pheromone B like (BAR,BBR,RCB,PRA), Fungal pheromone M- and P-Factor, Fungal pheromone other.

Class E cAMP receptors (Dictyostelium):

Frizzled/Smoothened family: frizzled, Smoothened,

Putative families: Ocular albinism proteins, Insect odorant receptors, Plant Mlo receptors, Nematode chemoreceptors, Vomeronasal receptors (V1R & V3R), Taste receptors T2R.

Orphans: Putative / unclassified GPCRs.

Non-GPCR families: Class Z Bacteriorhodopsins

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hedgehog and smoothened

MOLECULAR BIOLOGY: ON HEDGEHOG PROTEINS: "Signal transmission from membrane to cytoplasm proceeds through recruitment, by the seven-transmembrane protein Smoothened, of an atypical kinesin, which routes pathway activation by interaction with other components of a complex that includes the latent zinc finger transcription factor, Ci."

organogenesis

MOLECULAR BIOLOGY: ON HEDGEHOG PROTEINS: "The progress of organogenesis is governed by patterning processes that have occurred earlier during development and that involve the action of cell-cell signaling pathways, growth factors acting between cells, and transcription factors acting within cells. "

phosphorylation switches

Molecular Mechanisms of Signal Transduction : "The majority of signal transduction in bacteria occurs through pathways known as 'two-component' systems. These systems utilize a common mechanism involving transfer of a high-energy phosphoryl group from a histidine protein kinase to an aspartate residue of a response regulator protein. Response regulator proteins typically contain two domains: a regulatory domain and an effector domain. The regulatory domains of response regulator proteins can be thought of as phosphorylation-activated switches that are turned on and off by phosphorylation and dephosphorylation. In the active, phosphorylated state, the conserved regulatory domains activate effector domains to elicit specific responses such as flagellar rotation, regulation of transcription, or enzymatic catalysis. Phosphorylation alters the conformation of the regulatory domain, and the altered molecular surface is exploited for regulatory protein-protein interactions. " Link to link-to-images.

phosphotransfer-mediated signaling pathways

Histidine kinases and response regulator proteins in two-component signaling systems. : "Phosphotransfer-mediated signaling pathways allow cells to sense and respond to environmental stimuli. Autophosphorylating histidine protein kinases provide phosphoryl groups for response regulator proteins which, in turn, function as molecular switches that control diverse effector activities. Structural studies of proteins involved in two-component signaling systems have revealed a modular architecture with versatile conserved domains that are readily adapted to the specific needs of individual systems."

West AH, Stock AM.
Histidine kinases and response regulator proteins in two-component signaling systems.
Trends Biochem Sci. 2001 Jun;26(6):369-76.

response regulator proteins in bacteria

Molecular Mechanisms of Signal Transduction : "The majority of bacterial response regulator proteins are transcription factors that serve as repressors or activators to regulate the expression of specific genes. The effector domains of these response regulators are DNA-binding domains that can be categorized into three major families based on sequence and structural similarity.

The OmpR/PhoB family of response regulator transcription factors, distinguished by a winged-helix DNA-binding domain, is the largest family, accounting for ~45 percent of all response regulators. Most characterized members of this family have been shown to bind as tandem dimers to direct repeat DNA recognition sequences. . . Phosphorylation induces dimerization or higher-order oligomerization of the proteins and that dimerization is mediated by the phosphorylated regulatory domains. The activated regulatory domains of Escherichia coli ArcA, KdpE, PhoB, PhoP, and TorR and T. maritima DrrB and DrrD all exist as dimers with identical alpha4-beta5-alpha5 interfaces. In all cases, the dimerization interface is formed by a few hydrophobic residues surrounded by an extensive network of intra- and intermolecular salt bridges. The residues involved in these interactions are highly conserved in all members of the OmpR/PhoB family, but not in other response regulators. It is proposed that this mode of dimerization is common to most members of the OmpR/PhoB family and that it represents a family-specific mechanism for activation of DNA binding. Upon phosphorylation, the interface between regulatory and DNA-binding domains is disrupted, allowing the regulatory domains to dimerize via their alpha4-beta5-aalpha5 faces. Disruption of the interdomain interface frees the DNA-binding domain, allowing it to dimerize in tandem on direct repeat DNA half-sites with symmetry that is different from that of the regulatory domain dimer. Additional nuclear magnetic resonance (NMR) and biochemical studies support this mechanism of activation. " Link to link-to-images.

signal transduction or stimulus-response coupling

Molecular Mechanisms of Signal Transduction: "All living cells monitor their surrounding environments and elicit appropriate responses to changing conditions. Such stimulus-response coupling is essential for numerous and diverse processes such as growth and development, metabolic regulation, and sensing. Signal transduction pathways, through which information is passed sequentially from one protein component to the next, provide the molecular mechanism for linking input signals to output responses. Despite great diversity in the types of stimuli and responses involved in different pathways, a limited number of fundamental molecular strategies are used for signal transduction. One such strategy is reversible covalent modification, a process that regulates the activities of proteins. "

Wnt signalling

Wnt Signaling Controls The Fate Of Stem Cells In Adult Brains: "Wnt proteins form a family of highly conserved signaling molecules that play a crucial role in controlling cell expansion and lineage decisions in many types of stem cells."

Forgotten by evolution?: "the scientists, using certain substances, were able to bring the stem cell line to express proteins characteristic of muscle cells. Interestingly, when a particular path, known as the wnt-signal path, was stimulated, the cells began to develop the features of heart muscle cells. In contrast, when they were beforehand stimulated with a protein known as CDO, the cells showed certain characteristics of skeleton muscle cells."