J Neurophysiol (May 1, 2003). 10.1152/jn.00713.2002
Submitted on Submitted 21 August 2002; accepted in final form 24 October 2002

Fast Ca²⁺-Induced Potentiation of Heat-Activated Ionic Currents Requires cAMP/PKA Signaling and Functional AKAP Anchoring

 ¹Institute of Physiology and Experimental Pathophysiology, D-91054 Erlangen;  ²Department for Anatomy I, D91054 Erlangen; and  ³Institute for Anatomy and Cell Biology, D-35392 Giessen, Germany

Distler, C., P. K. Rathee, K. S. Lips, O. Obreja, W. Neuhuber, and M. Kress. Fast Ca²⁺-Induced Potentiation of Heat-Activated Ionic Currents Requires cAMP/PKA Signaling and Functional AKAP Anchoring. J. Neurophysiol. 89: 2499-2505, 2003. Calcium influx and the resulting increase in intracellular calcium concentration ([Ca²⁺]_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 [Ca²⁺]_i-activated calcium-dependent AC and caused translocation of catalytic protein kinase A subunit. Elevation of [Ca²⁺]_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 [Ca²⁺]_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.