ION CHANNELS--RECEPTORS AND SECOND MESSENGERS IN THE NERVOUS SYSTEM

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Calcium, sodium, potassium, and magnesium, ions can serve after translocation through ion channels or by transport proteins as second messengers to cause activation of release processes, contractile proteins, adenylate and guanylate cyclase, phosphodiesterases, protein kinases, phospholipases, ATPases and other enzymes. Receptors of various types an various toxins serve to modulate ion channels and generation of second messengers. Maitotoxin (MTX) activates calcium uptake and phosphoinositide breakdown in a wide range of cells. The two responses appear to be independent actions of MTX in that MTX-elicited calcium uptake can be greatly inhibited with no effort on MTX-elicited phosphoinositide breakdown. Lower concentrations of MTX (30 pM) are required to elicit phosphoinositide breakdown than are required to elicit significant calcium uptake. A radiolabelled MTX has been prepared and is being investigated in binding studies. In insulinoma cells MTX-elicited release of insulin appears due to release of @calcium from internal stores as a result of phosphoinositide breakdown and Generation of inositol trisphosphate (IP 3 ). MTX-elicited influx of calcium in insulinoma cells appears nonessential to release since it can be blocked by nifedipine without blocking release. Remarkably, cinnarizine blocks calcium influx and release it appears to block release by blocking Ip(3)-induced release of internal calcium. Local anesthetics enhance incorporation of radioactive inositol into phospholipids apparently by enhancing an exchange pathway. Forskolin and analogs are noncompetitive blockers of ganglionic nicotinic receptor channel complexes in pheochromocytoma cells, but unlike other non- competitive blockers do not enhance desensitization. An irreversible local anesthetic, proparacaine isothiocyanate, inhibits binding of a radioactive batrachotoxin to sodium channels to a much granter extent than inhibition of batrachotoxin-elicited sodium flux, indicating a large excess of sodium channels in synaptoneurosomes beyond those needed to induce a maximal influx of sorlium.