A Memory for Extracellular Ca 2 1 by Speeding Recovery of P 2 X Receptors from Desensitization

Nerve endings of nociceptors (pain-sensing neurons) express an unusual subtype of ATP-gated ion channel, the P2X3 receptor, that rapidly desensitizes (,100 msec) and slowly recovers (.20 min). Here we show that Ca, or certain other polyvalent cations, binds to an extracellular site on rat sensory neurons and can increase current through P2X3 channels more than 10-fold. Importantly, Ca facilitates P2X3 current to precisely the same level whether a transient Ca change occurred just before or several minutes before activating the channels with ATP. This memory for past changes in Ca is integrative in that a 90 sec Ca stimulus delivered just before an ATP application has the same effect as an earlier series of three, separated 30 sec Ca stimuli. These diverse phenomena are explained by a single mechanism: Ca speeds recovery of P2X channels from desensitization. Recovery follows an exponential growth curve that depends on the duration, but not the timing, of changes in recovery rate. Modulation of desensitization underlies a well described short-term memory in bacteria, and it might be similarly used in the nervous system.