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bioRxiv · 10.1101/2023.05.31.543017

ACTIVATION OF CYCLIN-DEPENDENT KINASE 5 BROADENS ACTION POTENTIALS IN HUMAN SENSORY NEURONS

Tiwari, M. N.·Hall, B. E.·Terse, A.·Amin, N.·Chung, M.-K.·Kulkarni, A.
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Abstract

Chronic pain is one of the most devastating and unpleasant conditions, associated with many pathological conditions. Tissue or nerve injuries induce comprehensive neurobiological plasticity in nociceptive neurons, which leads to chronic pain. Recent studies suggest that cyclin-dependent kinase 5 (CDK5) in primary afferents is a key neuronal kinase that modulates nociception through phosphorylation-dependent manner under pathological conditions. However, the impact of the CDK5 on nociceptor activity especially in human sensory neurons are not known. To determine the CDK5-mediated regulation of human dorsal root ganglia (hDRG) neuronal properties, we have performed the whole-cell patch clamp recordings in neurons dissociated from hDRG. CDK5 activation induced by overexpression of p35 depolarized the resting membrane potential and reduced the rheobase currents as compared to the uninfected neurons. CDK5 activation evidently changed the shape of the action potential (AP) by increasing AP rise time, AP fall time, and AP half width. The application of a prostaglandin E2 (PG) and bradykinin (BK) cocktail in uninfected hDRG neurons induced the depolarization of RMP and the reduction of rheobase currents along with increased AP rise time. However, PG and BK applications failed to induce any further significant changes in addition to the aforementioned changes of the membrane properties and AP parameters in the p35-overexpressing group. We conclude that CDK5 activation through the overexpression of p35 in dissociated hDRG neurons broadens AP in hDRG neurons and that CDK5 may play important roles in the modulation of AP properties in human primary afferents under pathological conditions, contributing to chronic pain.

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Tiwari, M. N., Hall, B. E., Terse, A., Amin, N., Chung, M.-K., Kulkarni, A.. 2023-06-01. ACTIVATION OF CYCLIN-DEPENDENT KINASE 5 BROADENS ACTION POTENTIALS IN HUMAN SENSORY NEURONS. https://doi.org/10.1101/2023.05.31.543017

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