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CELLULAR AND MOLECULAR

Augmentation of Ca_v3.2 T-Type Calcium Channel Activity by cAMP-Dependent Protein Kinase A

Department of Life Science (J.-A.K., J.-Y.P., H.-W.K., S.-U.H., J.-H.L.) and Interdisciplinary Program of Integrated Biotechnology (J.-A.K., J.-H.L.), Sogang University, Seoul, Korea; and Department of Physiology, Institute of Basic Medical Science, Yonsei University Wonju College of Medicine, Ilsan-Dong Wonju, Korea (S.-W.J.)

Ca²⁺ influx through T-type Ca²⁺ channels is crucial for important physiological activities such as hormone secretion and neuronal excitability. However, it is not clear whether these channels are regulated by cAMP-dependent protein kinase A (PKA). In the present study, we examined whether PKA modulates Ca_v3.2 T-type channels reconstituted in Xenopus oocytes. Application of 10 µM forskolin, an adenylyl cyclase stimulant, increased Ca_v3.2 channel activity by 40 ± 4% over 30 min and negatively shifted the steady-state inactivation curve (V₅₀ = -61.4 ± 0.2 versus -65.5 ± 0.1 mV). Forskolin did not affect other biophysical properties of Ca_v3.2 channels, including activation curve, current kinetics, and recovery from inactivation. Similar stimulation was achieved by applying 200 µM 8-bromo-cAMP, a membrane-permeable cAMP analog. The augmentation of Ca_v3.2 channel activity by forskolin was strongly inhibited by preincubation with 20 µM N-[2-(4-bromocinnamylamino)ethyl]-5-isoquinoline (H89), and reversed by subsequent application of 500 nM protein kinase A inhibitor peptide. The stimulation of Ca_v3.2 channel activity by PKA was mimicked by serotonin when 5HT₇ receptor was coexpressed with Ca_v3.2 in Xenopus oocytes. Finally, using chimeric channels constructed by replacing individual cytoplasmic loops of Ca_v3.2 with those of the Na_v1.4 channel, which is insensitive to PKA, we localized a region required for the PKA-mediated augmentation to the II-III loop of the Ca_v3.2.

Address correspondence to: Dr. Jung-Ha Lee, Department of Life Science, Sogang University, Mapo-Gu, Sinsu-Dong 1, Seoul 121-742, Korea. E-mail: jhleem{at}sogang.ac.kr

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