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Ann Rittenhouse, Ph.D.Academic Role: Associate Professor
Faculty Appointment(s) In:
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Rotation Projectsp>My lab has been interested in N-type calcium (Ca) channels because of their special position in the nervous system. They coordinate electrical activity occurring at the cell membrane with underlying biochemical and transcriptional events. N-type Ca channels are found only in nerve cells and neuronally-derived tissues, are associated with the regulation of transmitter synthesis, and release from most presynaptic nerve endings. They are the most extensively modulated Ca channels in the brain in that more pathways exist for their modulation than for any other type. Because of their role in transmission and high degree of modulation, they may be a critical player in certain types of synaptic plasticity. Indeed, much of what is termed neural plasticity ultimately starts at synapses and involves Ca influx. N-type Ca channels display endogenous, heterogeneous activity, called modes, defined as patterns of activity that are stable for much longer periods of time (sec to min) than are transitions between channel closings and openings. Because transitions among modes result in qualitative changes in channel activity, these channels can be considered plastic.Students will use both whole cell and single channel patch clamp and molecular techniques to test aspects of our model that attempts to explain N-type Ca channel plasticity. The following assumptions can be tested using recombinant channels in HEK cells, or native channels in sympathetic, cortical and/or striatal neurons. 1) Modes are the result of reversible modification of the channel, e.g., phosphorylation/dephosphorylation, G-protein binding/dissociation, etc. 2) Signaling cascades that converge at a critical site on the channel, such as a phosphorylation site, are predicted to affect the same mode. 3) Modification of the channel at one site is independent of modifications occurring at other sites. 4) Modification of the channel at multiple sites may occur simultaneously, giving rise to these complex patterns of activity. 5) Complex activity can be deconstructed into simpler, reversible reactions.  Figure 1. Schematic of N-type Ca channel modulation in sympathetic neurons. The transmitters listed exert their actions on Ca channels by activating signal transduction cascades that stimulate/liberate one or more of the following signaling molecules: AA, PKC and the G-protein subunits Gao and Gbg. Multi-transmitter effects may converge on these channels in cell bodies during presynaptic release of acetylcholine and peptides or in endings due to feedback from released norepinephrine and peptides. The implication of this model is that these layers of variability, observed at the level of the N-type Ca channel activity, may be building blocks that underlie emergent forms of plasticity, observed at the level of synapses and neural circuits. Moreover, some of the signaling cascades, which converge to modulate N-type Ca channel activity, are pathways that appear disrupted in certain disorders such as Alzheimer's Disease, schizophrenia and stroke. Thus, understanding these basic principles of channel modulation may reveal insights into these disorders. Selected Lab ReferencesLiwang Liu and Ann R. Rittenhouse (2000) Effects of Arachidonic Acid on Unitary Calcium Currents in Rat Sympathetic Neurons. J. Physiology, 525: 391- 404.
Office: S4-216
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55 Lake Avenue North Worcester, MA 01605