St-Ht31 P, an AKAP inhibitor

2018-10-09

Introduction 

The peptide st-Ht31 P, A-kinase anchoring protein (AKAP) inhibitor, has the negative control for st-Ht31. In DRG sensory neurons, the st-Ht31 P attenuated forskolin-stimulated translocation of the protein kinase A (PKA) catalytic subunit to the plasma membrane. Besides, st-Ht31 P attenuates the Ca2+-induced potentiation of Iheat in cultured DRG sensory neurons.

Pharmacologic action

The Research shows st-Ht31 P does not contain the proper amino acid sequence. It has no discernable effect on apoptosis and does not affect the anti-apoptotic effect of PTH1–34 (PTH's binding to its cell surface receptor results in the production of cyclic adenosine monophosphate (cAMP), which then activates PKA). Furthermore, the rats treated with st-Ht31 P /vehicle failed to display antinociceptive properties, which demonstrated that st-Ht31 P serves to attenuate PGE2-stimulated thermal hyperalgesia in a behavioral model. The first known behavioral test of the st-Ht31 P associative inhibitor are expected to spur further studies with this agent.

Function

The forskolin-induced potentiation of Iheat in HEK293 cells expressing TRPV1 was blocked following treatment with st-Ht31 P, indicating the administration of the ''A-kinase anchoring protein (AKAP) inhibitor" st-Ht31 P attenuated forskolin-stimulated translocation of the protein kinase A (PKA) catalytic subunit to the plasma membrane. Besides, the st-Ht31 P attenuates Ca2+-induced potentiation of Iheat in cultured DRG sensory neurons, further suggesting a role for AKAP. The control peptide, st-Ht31 P, is ineffective at disrupting PKA anchoring to AKAPs.

Pharmacokinetics and metabolism

In the experiment, rats were first analyzed for potential algesic responses to 50 μl injections of the st-Ht31 P inhibitor at 500, 50 and 5 μmol dosages. The result showed that the inhibitor did not elicit any significant differences in basal withdrawal latencies relative to Tris/saline vehicle. And the inhibitor st-Ht31 P did not elicit any significant differences in basal withdrawal latencies relative to Tris/saline vehicle. The rats injected with st-Ht31 P (50 μmol /50 μl injection) produced a near complete-blockade of PGE2 (0.3 μg/50 μl injection)-induced thermal hypersensitivity, with paw withdrawal levels indistinguishable from rats treated with vehicle/vehicle.

References:

Gorshkov, K., Mehta, S., Ramamurthy, S., Ronnett, G. V., Zhou, F. Q., & Zhang, J. (2017). AKAP-mediated feedback control of cAMP gradients in developing hippocampal neurons. Nature chemical biology, 13(4), 425.

Vincent, P., & Castro, L. R. (2017). Signaling: Spatial regulation of axonal cAMP. Nature chemical biology, 13(4), 348.

Jeske, N. A., Diogenes, A., Ruparel, N. B., Fehrenbacher, J. C., Henry, M., Akopian, A. N., & Hargreaves, K. M. (2008). A-kinase anchoring protein mediates TRPV1 thermal hyperalgesia through PKA phosphorylation of TRPV1. Pain, 138(3), 604-616.

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