Fast Ca2+-induced potentiation of heat-activated ionic currents requires cAMP/PKA signaling and functional AKAP anchoring.
Calcium influx and the resulting increase in intracellular calcium concentration ([Ca(2+)](i)) can induce enhanced sensitivity to temperature increases in nociceptive neurons. This sensitization accounts for heat hyperalgesia that is regularly observed following the activation of excitatory inward currents by pain-producing mediators. Here we show that rat sensory neurons express calcium-dependent adenylyl cyclases (AC) using RT-PCR and nonradioactive in situ hybridization. Ionomycin-induced rises in [Ca(2+)](i)-activated calcium-dependent AC and caused translocation of catalytic protein kinase A subunit. Elevation of [Ca(2+)](i) finally resulted in a significant potentiation of heat-activated currents and a drop in heat threshold. This was not prevented in the presence of suramin that nonspecifically uncouples G protein-dependent receptors. The sensitization was, however, inhibited when the specific PKA antagonist PKI(14-22) was added to the pipette solution or when PKA coupling to A kinase anchoring protein (AKAP) was disrupted with InCELLect StHt-31 uncoupling peptide. The results show that heat sensitization in nociceptive neurons can be induced by increases in [Ca(2+)](i) and requires PKA that is functionally coupled to the heat transducer, mostly likely vanilloid receptor VR-1. This calcium-dependent pathway can account for the sensitizing properties of many excitatory mediators that activate cationic membrane currents.
Institute of Physiology and Experimental Pathophysiology, D-91054 Erlangen, Germany.
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D000262:Adenylyl Cyclases / Q000096:biosynthesis; D000818:Animals; D002118:Calcium / Q000494:pharmacology*; D020013:Calcium Signaling / Q000502:physiology*; D000242:Cyclic AMP / Q000502:physiology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology*; D004594:Electrophysiology; D005260:Female; D019084:Fluorescent Antibody Technique, Indirect; D005727:Ganglia, Spinal / Q000166:cytology / Q000201:enzymology / Q000502:physiology; D006358:Hot Temperature; D017403:In Situ Hybridization; D007473:Ion Channels / Q000187:drug effects / Q000502:physiology*; D015759:Ionomycin / Q000494:pharmacology; D007476:Ionophores / Q000494:pharmacology; D009475:Neurons, Afferent / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction
D007473:Ion Channels; D007476:Ionophores; D015759:Ionomycin; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D000262:Adenylyl Cyclases; D002118:Calcium