▪ Abstract In the mid to late 1980s, studies were published that provided the first evidence for the existence of glutamate receptors that are not ligand-gated cation channels but are coupled to effector systems through GTP-binding proteins. Since those initial reports, tremendous progress has been made in characterizing these metabotropic glutamate receptors (mGluRs), including cloning and characterization of cDNA that encodes a family of eight mGluR subtypes, several of which have multiple splice variants. Also, tremendous progress has been made in developing new highly selective mGluR agonists and antagonists and toward determining the physiologic roles of the mGluRs in mammalian brain. These findings have exciting implications for drug development and suggest that the mGluRs provide a novel target for development of therepeutic agents that could have a significant impact on neuropharmacology.

Pharmacology and functions of metabotropic glutamate receptors.

Microglial cells are the resident macrophages in the central nervous system. These cells of mesodermal/mesenchymal origin migrate into all regions of the central nervous system, disseminate through the brain parenchyma, and acquire a specific ramified morphological phenotype termed "resting microglia." Recent studies indicate that even in the normal brain, microglia have highly motile processes by which they scan their territorial domains. By a large number of signaling pathways they can communicate with macroglial cells and neurons and with cells of the immune system. Likewise, microglial cells express receptors classically described for brain-specific communication such as neurotransmitter receptors and those first discovered as immune cell-specific such as for cytokines. Microglial cells are considered the most susceptible sensors of brain pathology. Upon any detection of signs for brain lesions or nervous system dysfunction, microglial cells undergo a complex, multistage activation process that converts them into the "activated microglial cell." This cell form has the capacity to release a large number of substances that can act detrimental or beneficial for the surrounding cells. Activated microglial cells can migrate to the site of injury, proliferate, and phagocytose cells and cellular compartments.

Physiology of Microglia

The metabotropic glutamate receptors: structure and functions.

Overview of general physiologic features and functions of vitamin D

http://www.columbia.edu/cu/biology/courses/g4008x/readings03/genomics/Zuker%20Sweet%20TRs%202001.pdf

Mammalian sweet taste receptors

Maintenance of a stable internal environment within complex organisms requires specialized cells that sense changes in the extracellular concentration of specific ions (such as Ca2+). Although the molecular nature of such ion sensors is unknown, parathyroid cells possess a cell surface Ca(2+)-sensing mechanism that also recognizes trivalent and polyvalent cations (such as neomycin) and couples by changes in phosphoinositide turnover and cytosolic Ca2+ to regulation of parathyroid hormone secretion. The latter restores normocalcaemia by acting on kidney and bone. We now report the cloning of complementary DNA encoding an extracellular Ca(2+)-sensing receptor from bovine parathyroid with pharmacological and functional properties nearly identical to those of the native receptor. The novel approximately 120K receptor shares limited similarity with the metabotropic glutamate receptors and features a large extracellular domain, containing clusters of acidic amino-acid residues possibly involved in calcium binding, coupled to a seven-membrane-spanning domain like those in the G-protein-coupled receptor superfamily.

Cloning and characterization of an extracellular Ca 2+ -sensing receptor from bovine parathyroid

Fluorescence and electrophysiological methods were used to deter- mine the effects of intracellular pH (pHi) on cellular NH~/K ÷ transport pathways in the renal medullary thick ascending limb of Henle (MTAL) from CD1 mice. Studies were performed in suspensions of MTAL tubules (S-MTAL) and in isolated, perfused MTAL segments (IP-MTAL). Steady-state pH i measured using 2,7-biscar- boxyethyl-5(6)-carboxyfluorescein (BCECF) averaged 7.42 -+ 0.02 (mean -+ SE) in S-MTAL and 7.26 - 0.04 in IP-MTAL. The intrinsic cellular buffering power of MTAL cells was 29.7 -+ 2.4 mM/pHi unit at pHi values between 7.0 and 7.6, but below a pH~ of 7.0 the intrinsic buffering power increased linearly to ~ 50 mM/pH~ unit at pH i 6.5. In IP-MTAL, NH~ entered cells across apical membranes via both Ba2÷-sensitive pathway and furosemide-sensitive Na+:K+(NH~):2C1 - cotransport mechanisms. The K0.5 and maximal rate for combined apical entry were 0.5 mM and 83.3 raM/rain, respectively. The apical Ba2+-sensitive cell conductance in IP-MTAL (Go), which reflects the apical K ÷ conductance, was sensitive to pHi over a pHi range of 6.0-7.4 with an apparent K05 at pH i ~ 6.7. The rate of cellular NH~ influx in IP-MTAL due to the apical Ba2*-sensitive NH~ transport pathway was sensitive to reduction in cytosolic pH whether pHi was changed by acidifying the basolateral medium or by inhibition of the apical Na÷:H ÷ exchanger with amiloride at a constant pH o of 7.4. The pHi sensitivities of Gc and apical, Ba2÷-sensitive NH~ influx in IP-MTAL were virtually identical. The pH~ sensitivity of the Ba2+-sensitive NH~ influx in S-MTAL when exposed to (apical + basolateral) NH4CI was greater than that observed in IP-MTAL where NH4C1 was added only to apical membranes, suggesting an additional effect of intracellular NH~/NH s on NH~" influx. NH~ entry via apical Na+:K÷(NH;):2CI - cotransport in IP-MTAL was somewhat more sensitive to reductions in pH~ than the Ba~÷-sensitive NH~ influx pathway; NH~ entry decreased by 52.9 -+ 13.4% on reducing pH i from 7.31 +- 0.17 to 6.82 - 0.14. These results suggest that pH~ may provide a negative feedback signal for regulating

Adam Sun

Papers

Cloning and characterization of an extracellular Ca 2+ -sensing receptor from bovine parathyroid

Cellular NH /K + Transport Pathways in Mouse Medullary Thick Limb of Henle

Volume Regulation in Renal Medullary Nephron Segments