Wiley Interdisciplinary Reviews. Membrane Transport and Signaling

L-type calcium channels (Cav1) represent one of the three major classes (Cav1-3) of voltage-gated calcium channels. They were identified as the target of clinically used calcium channel blockers (CCBs; so-called calcium antagonists) and were the first class accessible to biochemical characterization. Four of the 10 known α 1 subunits (Cav1.1-Cav1.4) form the pore of L-type calcium channels (LTCCs) and contain the high-affinity drug-binding sites for dihydropyridines and other chemical classes of organic CCBs...

The study of biological form and how it arises is the domain of the developmental biologists; but once the form is achieved, the organ poses a fascinating conundrum for all the life scientists: how are form and function maintained in adult organs throughout most of the life of the organism? That they do appears to contradict the inherently plastic nature of organogenesis during development. How do cells with the same genetic information arrive at, and maintain such different architectures and functions, and how do they keep remembering that they are different from each other? It is now clear that narratives based solely on genes and an irreversible regulatory dynamics cannot answer these questions satisfactorily, and the concept of microenvironmental signaling needs to be added to the equation...

Voltage-gated Ca(2+) (CaV) channels mediate Ca(2+) ions influx into cells in response to depolarization of the plasma membrane. They are responsible for initiation of excitation-contraction and excitation-secretion coupling, and the Ca(2+) that enters cells through this pathway is also important in the regulation of protein phosphorylation, gene transcription, and many other intracellular events. Initial electrophysiological studies divided CaV channels into low-voltage-activated (LVA) and high-voltage-activated (HVA) channels...

Proton channels are expressed in all cells of the immune system to various degrees. While their function in phagocytic cells, immune cells that engulf bacteria and cell debris for clearance, has been the object of extensive research, the function of proton channels in non-phagocytic cells has remained more elusive until recently. Further studies have been helped by the discovery of the gene coding for the mammalian proton channel, HVCN1 , which has prompted a new wave of research in this area. Recent findings show how proton channels regulate cell function in non-phagocytic cells of the immune system such as basophils and lymphocytes...

The 41(st) family of solute carriers (SLC41) comprises three members A1, A2 and A3, which are distantly homologous to bacterial Mg(2+) channel MgtE. SLC41A1 was recently characterized as being an Na(+)/Mg(2+) exchanger (NME; a predominant cellular Mg(2+) efflux system). Little is known about the exact function of SLC41A2 and SLC41A3, although, these proteins have also been linked to Mg(2+) transport in human (animal) cells. The molecular biology (including membrane topology, cellular localization, transcriptomics and proteomics) of SLC41A2 and SLC41A3 compared with SLC41A1 has only been poorly explored...

The endocrine system is the system of ductless glands and single cells that synthetize hormones and release them directly into the bloodstream. Regulation of endocrine system is very complex and ATP and its degradable products ADP and adenosine contribute to its regulation acting as extracellular messengers for purinergic receptors. These include P2X receptors, a family of ligand-gated ion channels which expression and roles in endocrine tissues are reviewed here. There are seven mammalian purinergic receptor subunits, denoted P2X1 through P2X7, and the majority of these subunits are also expressed in secretory and non-secretory cells of endocrine system...

The "Bystander" and "Good Samaritan" effects involve the transfer of toxic or beneficial compounds from one cell to a generally adjacent other through gap junction channels and through extracellular routes. The variety of injuries in which bystander cell killing or protection occurs has greatly expanded in the last decade to include infectious agents and therapeutic compounds, radiation injury, chaperones in cell therapy and apoptosis in development. This has been accompanied by the appreciation that both gap junction mediated and paracrine routes are used for the signaling of the "kiss of life" and the "kiss of death" and that manipulations of these pathways and the molecules that use them may find therapeutic utility in treatment of a variety of pathological conditions...

P2Y receptors are G protein-coupled receptors (GPCRs) that are activated by adenine and uridine nucleotides and nucleotide sugars. There are eight subtypes of P2Y receptors (P2Y1, P2Y2, P2Y4, P2Y6, P2Y11, P2Y12, P2Y13, and P2Y14), which activate intracellular signaling cascades to regulate a variety of cellular processes, including proliferation, differentiation, phagocytosis, secretion, nociception, cell adhesion, and cell migration. These signaling cascades operate mainly by the sequential activation or deactivation of heterotrimeric and monomeric G proteins, phospholipases, adenylyl and guanylyl cyclases, protein kinases, and phosphodiesterases...

There are eight subtypes of P2Y receptors (P2YRs) that are activated, and in some cases inhibited, by a range of extracellular nucleotides. These nucleotides are ubiquitous, but their extracellular concentration can rise dramatically in response to hypoxia, ischemia, or mechanical stress, injury, and release through channels and from vesicles. Two subclasses of P2YRs were defined based on clustering of sequences, second messengers, and receptor sequence analysis. The numbering system for P2YR subtypes is discontinuous; i...

Glutamate, a key neurotransmitter in the vertebrate retina, acts via ionotropic and metabotropic receptors. Retina expresses mRNA for all metabotropic glutamate receptors and proteins for all but mGluR3. Every retinal cell class expresses one or more of these receptors. In general, these receptors are present presynaptically and serve to modulate synaptic transmission. While mGluRs on the photoreceptor terminal act as autoreceptors to titer glutamate levels, those on horizontal cell processes seem to shape the light response...

The low numbers of hydrogen ions in physiological solutions encouraged the assumption that H(+) currents flowing through conductive pathways would be so small as to be unmeasurable even if theoretically possible. Evidence for an H(+)-based action potential in the luminescent dinoflagellate Noctiluca and for an H(+)-conducting channel created by the secretions of the bacterium Bacillus brevis, did little to alter this perception. The clear demonstration of H(+) conduction in molluscan neurons might have provided the breakthrough but the new pathway was without an easily demonstrable function, and escaped general attention...

The biophysical properties of the voltage gated proton channel (H(V)1) are the key elements of its physiological function. The voltage gated proton channel is a unique molecule that in contrast to all other ion channels is exclusively selective for protons. Alone among proton channels, it has voltage and time dependent gating like other "classical" ion channels. H(V)1 is furthermore a sensor for the pH in the cell and the surrounding media. Its voltage dependence is strictly coupled to the pH gradient across the membrane...

In the developing embryo, appropriate patterning of the endoderm fated to become pancreas requires the spatial and temporal coordination of soluble factors secreted by the surrounding tissues. Once pancreatic progenitor cells are specified in the developing gut tube epithelium, epithelial-mesenchymal interactions, as well as a cascade of transcription factors, subsequently delineate three distinct lineages, including endocrine, exocrine and ductal cells. Simultaneous morphological changes, including branching, vascularization, and proximal organ development, also influence the process of specification and differentiation...

It is now accepted that extracellular ATP and other nucleotides are potent signaling molecules, akin to neurotransmitters, hormones and lipid mediators. In the liver, several clues support a significant role for extracellular ATP-induced signaling pathways in the control of tissue homeostasis. First, ATP and other nucleotides are physiologically detected in extracellular fluids within the liver, including sinusoidal blood and intraductular bile, in various mammalian species including human and rodents. Moreover, finely tuned mechanisms of ATP release by different liver cell types have been described, under physiological cellular changes...

Historically, brain catecholamine systems have been the primary focus of studies examining the neural substrates of drug addiction. In the past two decades, however, a wealth of evidence has accumulated indicating a pivotal role for glutamatergic neurotransmission in mediating addictive behaviors as well as long-term neuroplasticity associated with chronic drug use. As a result, there has been increased interest in developing glutamate-based therapies for the treatment of addictive disorders. Metabotropic glutamate (mGlu) receptors are classified into subcategories designated as Group I (mGlu1 and mGlu5), Group II (mGlu2 and mGlu3), and Group III (mGlu4, mGlu6, mGlu7, and mGlu8), and have received a great deal of attention due to their mediation of slower modulatory excitatory neurotransmission...

The properties of the voltage-dependent H(+) channel have been studied in lung epithelial cells for many years, and recently HVCN1 mRNA expression has been linked directly to H(+) channel function in lung epithelium. The H(+) channel is activated by strong membrane depolarization, intracellular acidity, or extracellular alkalinity. Early on it was noted that these are surprising physiological channel characteristics when considering that lung epithelial cells have rather stable membrane potentials and a well pH-buffered intracellular milieu...

G-protein coupled receptors (GPCR) represent a class of therapeutic targets that have been widely exploited for drug designs and development. Metabotropic glutamate receptors (mGluRs) belong to Class C GPCRs and are predominantly involved in maintaining cellular homeostasis in the central nervous system (CNS). The surprising accumulating evidence suggesting other functional roles of mGluRs in human malignancies in addition to synaptic transmission has presented intriguing possibilities to make mGluRs putative novel targets for human cancers...

Metabotropic glutamate (mGlu) receptors are G-protein-coupled receptors, which include eight subtypes that have been classified into three groups (I-III) based upon sequence homology, signal transduction mechanism and pharmacological profile. Although most studied with regard to neuronal function and modulation, mGlu receptors are also expressed by neuroglia-including astrocytes, microglia and oligodendrocytes. Activation of mGlu receptors on neuroglia under both physiologic and pathophysiologic conditions mediates numerous actions that are essential for intrinsic glial cell function, as well as for glial-neuronal interactions...

Different types of ionotropic P2X purinoceptors are expressed in all major types of neuroglia, where they mediate a variety of physiological and pathological signaling. Cortical astrocytes express specific P2X1/5 heteromeric receptors that are activated by ongoing synaptic transmission and can trigger fast local signaling through elevation in cytoplasmic Ca(2+) and Na(+) concentrations. Oligodendrocytes express several types of P2X receptors that may control their development and mediate axonal-glial interactions...

Cerebral ischemia is a leading cause of death and long-term disabilities worldwide. Excessive intracellular Ca(2+) accumulation in neurons has been considered essential for neuronal injury associated with cerebral ischemia. Although the involvement of glutamate receptors in neuronal Ca(2+) accumulation and toxicity has been the subject of intensive investigation, inhibitors for these receptors showed little effect in clinical trials. Thus, additional Ca(2+) toxicity pathway(s) must be involved. Acidosis is a common feature in cerebral ischemia and was known to cause brain injury...