Several reports have demonstrated that SPP inhibits cell motility. SPP inhibited chemotactic motility of mouse melanoma B16, mouse fibroblast BALB/3T3 clone A31, and several tumor cell lines at nanomolar concentrations (17-19). Moreover, SPP immobilized on glass beads markedly inhibited melanoma cell motility. However, pertussis toxin treatment did not block the effect of SPP, suggesting that in these cells SPP acts through a cell surface receptor, independently of pertussis toxin-sensitive G-proteins (20). In contrast, SPP inhibits chemotaxis of human breast cancer cells only at high (micromolar) concentrations, acting independently of EDG-1 (21).We have recently identified SPP as a ligand for the G-protein-coupled receptor, endothelial differentiation gene-1 (EDG-1) (22). EDG-1 binds SPP with remarkable specificity and high affinity (K D ϭ 8 nM) (9,22). Binding of SPP to EDG-1 resulted in inhibition of adenylate cyclase and activation of mitogen-activated protein kinase (both G i -mediated), but did not mobilize calcium from internal stores (9, 23). In contrast, Okamoto et al. (12) found that in HEL cells overexpressing EDG-1, binding of SPP induced calcium mobilization (12).

In habitual smokers, smoking acutely reduces baseline levels of vagal-cardiac nerve activity and completely resets vagally mediated arterial baroreceptor-cardiac reflex responses. Smoking also reduces muscle sympathetic nerve activity but augments increases of sympathetic activity triggered by brief arterial pressure reductions. This pattern of autonomic changes is likely to influence smokers' responses to acute arterial pressure reductions importantly.

Heterogeneity among NPY (and PYY) receptors was first proposed on the basis of studies on sympathetic neuroeffector junctions, where NPY (and PYY) can exert three types of action: 1) a direct (e.g., vasoconstrictor) response; 2) a postjunctional potentiating effect on NE-evoked vasoconstriction; and 3) a prejunctional suppression of stimulated NE release; the two latter phenomena are probably reciprocal, since NE affect NPY mechanisms similarly. It was found that amidated C-terminal NPY (or PYY) fragments, e.g., NPY 13-36, could stimulate selectively prejunctional NPY/PYY receptors, which were termed Y2-receptors. Consequently, the postjunctional receptors which were activated poorly by NPY/PYY fragments, were termed Y1-receptors. Later work has indicated that the Y2-receptor may occur postjunctionally in selected sympathetic effector systems. The central nervous system appears to contain a mixture of Y1- and Y2-receptors as indicated by functional as well as binding studies. For instance, NPY and NPY 13-36 produced diametrically opposite effects on behavioral activity, indicating the action of the parent peptide on two distinct receptors. Cell lines, most importantly neuroblastomas, with exclusive populations of Y1- or Y2-receptors, have been characterized by binding and second messenger studies. In this work, selective agonists for the two receptor subtypes were used. Work of many investigators has formed the basis for subclassifying NPY/PYY effects being mediated by either Y1- or Y2-receptors. A preliminary subclassification based on effects of NPY, PYY, fragments and/or analogs is provided in Table 6. It is, however, to be expected that further receptor heterogeneity will be revealed in the future. It is argued that mast cells possess atypical NPY/PYY receptors. The histamine release associated with stimulation of the latter receptors may, at least in part, underlie the capacity of NPY as well as of short C-terminal fragments to reduce blood pressure. Fragments, such as NPY 22-36, appear to be relatively selective vasodepressor agents because of their weak vasopressor properties.(ABSTRACT TRUNCATED AT 400 WORDS)

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