CL/RAMP2 and CL/RAMP3 produce pharmacologically distinct adrenomedullin receptors:a comparison of effects of adrenomedullin 22-52, CGRP 8-37 and BIBN4096BS

1. Adrenomedullin (AM) has two known receptors formed by the calcitonin receptor-like receptor (CL) and receptor activity-modifying protein (RAMP) 2 or 3: We report the effects of the antagonist fragments of human AM and CGRP (AM 22-52 and CGRP 8-37) in inhibiting AM at human (h), rat (r) and mixed species CL/RAMP2 and CL/RAMP3 receptors transiently expressed in Cos 7 cells or endogenously expressed as rCL/rRAMP2 complexes by Rat 2 and L6 cells. 2. AM 22-52 (10 μM) antagonised AM at all CL/RAMP2 complexes (apparent pA 2 values: 7.34±0.14 (hCL/hRAMP2), 7.28±0.06 (Rat2), 7.00±0.05 (L6), 6.25±0.17(rCL/hRAMP2)). CGRP 8-37 (10 μM) resembled AM 22-52 except on the rCL/hRAMP2 complex, where it did not antagonise AM (apparent PA 2 values: 7.04±0.13 (hCL/hRAMP2), 6.72±0.06 (Rat2), 7.03±0. 12 (L6)). 3. On CL/RAMP3 receptors, 10 μM CGRP 8-37 was an effective antagonist at all combinations (apparent pA 2 values: 6.96±0.08 (hCL/hRAMP3), 6.18±0.18 (rCL/rRAMP3), 6.48±0.20 (rCL/ hRAMP3)). However, 10 μm AM 22-52 only antagonised AM at the hCL/hRAMP3 receptor (apparent PA 2 6.73±0.14). 4. BIBN4096BS (10 μM) did not antagonise AM at any of the receptors. 5. Where investigated (all-rat and rat/human combinations), the agonist potency order on the CL/ RAMP3 receptor was AM∼βCGRP>αCGRP. 6. rRAMP3 showed three apparent polymorphisms, none of which altered its coding sequence. 7. This study shows that on CL/RAMP complexes, AM 22-52 has significant selectivity for the CL/ RAMP2 combination over the CL/RAMP3 combination. On the mixed species receptor, CGRP 8-37 showed the opposite selectivity. Thus, depending on the species, it is possible to discriminate pharmacologically between CL/RAMP2 and CL/RAMP3 AM receptors.

New Binary Extremal Self-Dual Codes of Lengths 50 and 52

* This work was partially supported by the Bulgarian National Science Fund under Contract No. MM – 503/1995.

Medical School Donor Recognition Reception Photo 52

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Age determination of sediment core NP90-52 (Table 1)

Data on glacial erosion have been compiled and synthesised using a wide range of sediment budget and sediment yield studies from the Svalbard-Barents Sea region. The data include studies ranging in timescale from 1 to 10**6 yr, and in size of drainage basin from 101 to 105 km**2. They show a clear dependence of sediment yield on the mode of glacierization. Polar glaciers erode at rates comparable to those found in Arctic fluvial basins, or about 40 t/km**-2/ yr or 0.02 mm/yr. In contrast, rates of erosion by polythermal glaciers are 800-1000 t/km**2/ yr (or ca 0.3-0.4 mm/yr), while rates from fast-flowing glaciers are slightly more than twice this: 2100 t/km**2/yr (or 1 mm/yr). Similar rates are also found for large glacierized basins like those in the southwestern parts of the Barents Sea. In contrast to the situation in fluvial basins, in which sediment yield typically decreases with increasing basin size, the tendency in glacierized basins is for erosion to be independent of basin size. In studies of sediment yield from glaciers it is sometimes difficult to distinguish between material actually dislodged from the bedrock by glaciers and material dislodged by other processes in interglacial times and simply transported to a depocenter by a glacier. Our data suggest that pulses of sediment resulting from advance of a glacier over previously-dislodged material last on the order of 10**3 yr, and result in inferred erosion rates that are approximately 25% higher than long-term average rates of glacial erosion. The maximum sediment fluxes from the large Storfjorden and Bear Island drainage basins occurred in mid-Pleistocene. The onset of this period of high sediment yield coincided with the onset of the 100 kyr glacial cycle. We presume that this was the beginning of a period of increased glacial activity, but one in which glaciers still advanced and retreated frequently. During the last two to four 100 kyr cycles, however, sediment yields appear to have decreased. This decrease may be the result of the submergence of the Barents Sea. Glacier erosion would be much higher for a subaerial Barents Sea setting than it would be for a present day subsea Barents Sea. A classical question in Quaternary Geology is whether glaciers are more erosive than rivers. We surmise that if factors such as the lithology and the available potential energy (mgh) of the precipitation falling at a given altitude, whether in liquid or solid form, are held constant, then glaciers are vastly more effective agents of erosion than rivers.