A1 adenosine receptors (A1ARs) exert important effects in the central nervous system. However, the expression and function of A1ARs in oligodendrocyte precursor cells (OPCs) and oligodendrocytes (OLGs) is unclear. To address this issue, we examined A1AR expression during different stages of oligodendrocyte development. Radioreceptor studies showed that membranes prepared from OPCs and OLGs expressed high-affinity A1ARs with Kd values of 1.35 +/- 0.33 and 1.2 +/- 0.27 nM for [3H]CCPA, 1.17 +/- 0.24 and 1.4 +/- 0.34 nM for [3H]DPCPX, respectively. Bmax values were 64.31 +/- 6.14 and 75 +/- 6 fmol/mg protein for [3H]CCPA, and 153 +/- 12 and 205 +/- 17.8 fmol/mg protein for [3H]DPCPX, respectively. Activation of A1ARs using N6-cyclopentyladenosine (CPA) reduced both forskolin- and N-ethylcarboxyamidoadenosine (NECA)-stimulated cAMP accumulation, but did not affect basal cAMP levels. Activation of A1ARs by CPA stimulated OPC migration, but did not affect cell viability, proliferation, or differentiation. These results show that OPCs and OLGs express functional A1ARs that can stimulate the migration of OPCs.
A1 adenosine receptors (A1ARs) are widely expressed in the brain during development. To examine whether A1AR activation can alter postnatal brain formation, neonatal rats from postnatal days 3 to 14 were treated with the A1AR agonist N6-cyclopentyladenosine (CPA) in the presence or absence of the peripheral A1AR antagonist 8-(p-sulfophenyl)-theophylline (8SPT). CPA or CPA + 8SPT treatment resulted in reductions in white matter volume, ventriculomegaly, and neuronal loss. Quantitative electron microscopy revealed reductions in total axon volume following A1AR agonist treatment. We also observed reduced expression of myelin basic protein in treated animals. Showing that functional A1ARs were present over the ranges of ages studies, high levels of specific [3H]CCPA binding were observed at PD 4, 7 and 14, and receptor-G protein coupling was present at each age. These observations show that activation of A1ARs with doses of CPA that mimic the effects of high adenosine levels results in damage to the developing brain.
Tropical natives possess heat tolerance due to the ability to off-load endogenous and exogenous heat efficiently using a minimum amount of sweat. On the other hand, exposure of temperate natives to heat results in exaggerated production of sweat, of which part is lost by dripping and, thus, not available for evaporation. How sweating is modified in natives of temperate climate zones by prolonged residence in the tropics is not well-understood. The aim of this study was to investigate possible changes in the peripheral sweating mechanisms. Sweating responses to iontophoretically applied acetylcholine (ACh) were compared between Japanese subjects having either permanently resided in Japan (Japan resident Japanese, JRJ) or having stayed in the tropics for 2 years or longer (Tropics resident Japanese, TRJ). Quantitative sudomotor axon reflex tests by iontophoresis of ACh (10%, 2 mA for 5 min) were applied to determine directly activated (DIR) and axon reflex-mediated sweating during [AXR(1)] and after [AXR(2)] ACh iontophoresis. The sweat onset time of AXR(1) was 0.6 min shorter in JRJ than in TRJ (P<0.0001), and AXR(1) (P<0.0004), AXR(2) (P<0.0001), and DIR (P<0.0001) sweating responses were larger in JRJ than in TRJ. AXR and DIR sweating volumes (P<0.0001) were negatively correlated, and sweat onset times (P<0.0001) were positively correlated with the duration of residence in the tropics (2 to 13 years). The observed attenuation of sweating in TRJ suggests that temperate natives may acquire heat tolerance with improved sweating economy similar to tropical natives after prolonged residence in the tropics.
To identify binding partners of the A1AR (A1 adenosine receptor), yeast two-hybrid screening of a rat embryonic cDNA library was performed. This procedure led to the identification of erythrocyte membrane cytoskeletal protein (represented as 4.1G) as an A1AR-binding partner. Truncation studies revealed that the C-terminal domain of 4.1G was essential for binding to A1ARs and that the C-terminal domain of 4.1G and the third intracellular loop of A1ARs interacted. A1AR-4.1G interaction was also confirmed in studies using brain tissue. Studies in HEK-293 (human embryonic kidney 293) cells and Chinese-hamster ovary cells showed that 4.1G interfered with A1AR signal transduction, as 4.1G reduced A1AR-mediated inhibition of cAMP accumulation and intracellular calcium release. 4.1G also altered cell-surface A1AR expression. These observations identify 4.1G as a novel A1AR-binding partner that can regulate adenosine action.
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