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Primary nociceptors are specialized sensory neurons that detect and
signal painful noxious stimuli such as extreme heat or cold, damaging
mechanical force or chemical irritants. The properties of nociceptors
can be modified by local environment. For example, nociceptive sensory
fibers at the sites of tissue damage or inflammation become more sensitive
to excitation, thus contributing to hyperalgesia. It is widely believed
that the functional and structural modifications of primary nociceptors
are essential for various types of clinical pain, however the mechanisms
that govern these modifications are poorly understood.
Our research focuses on the
Ca2+ ion as the key player in controlling the activity-dependent plasticity
in nociceptors. Ca2+ is often referred to as a life and death signal
because
of its universal regulatory role in almost every aspect of cell function.
When Ca2+ enters neurons during excitation it binds to and gates several
types of Ca2+-regulated ion channels. This has an immediate effect on
neuronal excitability. Highly localized micromolar elevation of Ca2+
at the presynaptic site triggers neurotransmitter release and enables
communication between neurons. Smaller and more prolonged residual Ca2+
elevation at the release sites regulates synaptic plasticity. In the
soma, Ca2+ can activate transcription events thereby initiating long-term
molecular, structural and functional modifications to neurons.
We use a variety of experimental approaches, including Ca2+ digital
imaging, patch clamp recording, immunohistochemistry, gene manipulation
and DNA microarray techniques to carry out research in three areas:
1) Modulation of Ca2+ signaling in primary nociceptors by drugs, neurotransmitters
and second messengers; 2) Presynaptic Ca2+ signaling and the mechanisms
of synaptic plasticity at the sensory synapses following noxious stimulation;
3) Ca2+-dependent gene regulation in primary nociceptors, with emphasis
on the Ca2+-activated transcription factor NFAT. These studies will
provide insight into the mechanisms that underlie plasticity of pain-conducting
pathways and may identify new therapeutic targets for the treatment
of pain.
Representative Publications:
Schnizler, K., Shutov, L.P., Van Kanegan, M.J., Merrill, M.A., Nichols, B., McKnight, G.S., Strack, S., Hell, J.W., and Usachev, Y.M.: PKA anchoring via AKAP150 is essential for TRPV1 modulation by forskolin and prostaglandin E2 in mouse sensory neurons. Journal of Neuroscience 28(19):4904-4917, 2008.
Medvedeva, Y.V., Kim, M.-S., and Usachev, Y.M.: Mechanisms of prolonged presynaptic Ca2+ signaling and glutamate release induced by TRPV1 activation in rat sensory neurons. Journal of Neuroscience 28(20):5295-5311, 2008.
Usachev, Y.M., Marsh, A.J., Johanns, T.M., Lemke M.M., and Thayer, S.A.: Activation of protein kinase C in sensory neurons accelerates Ca2+ uptake into the endoplasmic reticulum. Journal of Neuroscience 26 (1):311-318, 2006.
Usachev Y.M., DeMarco S.J., Campbell C., Strehler E.E., Thayer S.A. Bradykinin and ATP accelerate Ca2+ efflux from rat sensory neurons via protein kinase C and the plasma membrane Ca2+ pump isoform 4. Neuron 33:113-122, 2002.
Usachev Y.M., Toutenhoofd S.L., Goellner G.M., Strehler E.E., Thayer S.A. Differentiation induces upregulation of plasma membrane Ca2+-ATPase and concomitant increase in Ca2+ efflux in human neuroblastoma cell line IMR-32. Journal of Neurochemistry 76:1756-1765, 2001.
Additional
publications
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