Department of Pharmacology and Physiology, UMDNJ New Jersey Medical School, 185 South Orange Avenue, Newark, NJ 07103, USA
(e-mail: thomasap{at}umdnj.edu; nowyckmc{at}umdnj.edu)
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Introduction |
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Voltage-independent Ca2+-permeable channels comprise the most numerous and varied Ca2+-influx pathways in cells. Many ligand-gated ionotropic channels are relatively non-selective for cations and can pass substantial amounts of Ca2+. Ionotropic receptors for the transmitters glutamate (NMDA; AMPA; kainate), acetylcholine (nAChR), serotonin (5HT3), and ATP (P2X) admit significant amounts of Ca2+. Store-operated channels (SOC) open in response to emptying of intracellular stores. Possible mechanisms of activation include interaction with the inositol (1,4,5)-trisphosphate [Ins(1,4,5)P3] receptor (IP3R), a diffusible Ca2+-influx factor (CIF) or channel insertion into the membrane. Ca2+-release-activated Ca2+ channel (CRAC) is found in cells of the blood lineage and is highly Ca2+-selective. Transient receptor potential channels (TRP) form a large, ancient family, that has been subdivided into three groups (TRPC, TRPV, TRPM). Most are nonspecific cation channels. TRPC channels respond indirectly to hormones and transmitters through phospholipase Cß (PLCß) activation and via second messengers such as diacylglycerol (DAG), spinghosine, ADP-ribose, arachidonic acid and other as yet unidentified signals. TRPV and TRPM families are directly or indirectly responsive to numerous sensory stimuli such as temperature and osmolarity.
Other voltage-independent channels respond to sensory stimuli. Hair cells of the ear have mechanically opened Ca2+-permeant channels. Light, odorants and taste molecules operate through a signal cascade that includes activation of adenylate (AC) and guanylate cyclase (GC), and subsequent opening or closing of cyclic-nucleotide-gated channels whose gating is regulated by the cyclic nucletotides cAMP or cGMP.
With a few exceptions (ligand-gated channels, mechanosensitive channels in
hair cells), voltage-independent pathways are generally activated by signaling
cascades. The most common pathway involves activation of phospholipase C (PLC)
and generation of Ins(1,4,5)P3 and DAG from
phosphatidylinositol (4,5)-bisphosphate [PtdIns(4,5)P2].
Hormones and neurotransmitters can bind to >1000 G-protein coupled
receptors (GPCR). The G subunit of the heterotrimeric Gq/11 family
activated PLCß. GPCR coupling to Gi/o can also activate PLCß, but
through the ß
subunits that are liberated in large quantities.
Other members of the PLC family can be activated by growth factors that
activate receptor tyrosine kinases (RTK; PLC
), Ras (PLC
), and
intracellular Ca2+ (PLC
). PLC
is also activated by
antigen stimulated activation of non-receptor tyrosine kinases such as Src via
binding to T-cell receptors (TCRs) and B-cell receptors (BCRs).
Ca2+ release from intracellular stores is mediated by ryanodine (RyR) and IP3R channels. These two types of intracellular channel have substantial homology in their transmembrane channel-forming domains, and at least three distinct isoforms of both RyR and IP3R have been identified. RyR are activated by a rise in intracellular Ca2+ Ca2+-induced Ca2+ release (CICR). In addition there are RyR-like channels activated by cyclic ADP-ribose (cADPR), sphingosine and a distinct Ca2+-release pathway activated by nicotinic acid adenine dinucleotide phosphate (NAADP).
Within Ca2+-storing organelles, Ca2+ ions are bound to specialized Ca2+-buffering proteins. These include calsequestrins (CS), calreticulins (CR) and calnexins (CN). In the cytosol, there are mobile Ca2+ buffers that blunt Ca2+ spikes and assist in redistribution of Ca2+ ions. These include the calbindins (CB), paravalbumin (PV), calmodulin and S100 protein families.
In contrast to the striking variety of mechanisms for inducing extracellular Ca2+ influx, Ca2+ extrusion to the extracellular space is largely limited to two families of proteins: the plasma membrane Ca2+ ATPase (PMCA) and the Na+/Ca2+ exchanger. Intracellular Ca2+ is also lowered by Ca2+ uptake into cellular organelles via a variety of organelle-specific pumps and transporters. Uptake into the ER is regulated by the sarco- and endoplasmic reticulum Ca2+ ATPase (SERCA) family. Uptake into mitochondria is mediated by the mitochondrial Ca2+-uniporter. Uptake into Golgi is mediated by the P-type Ca2+-transport ATPase (PMR1/ATP2C1). Mitochondria can release Ca2+ via the mitochondrial Na+-H+/Ca2+ exchanger and, under some circumstances, the permeability transition pore (PTP). As a result of the interplay between mitochondrial Ca2+ uptake and release pathways, these organelles are thought to play an important role in modulating cytosolic Ca2+ signals derived from other channels. Release from the Golgi and nuclear membrane takes place via intracellular channels similar to those found in the ER [IP3R, RyR].
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