4,571 research outputs found
Molecular Sensors and Modulators of Thermoreception
Peer reviewedPostprin
Comparing ion conductance recordings of synthetic lipid bilayers with cell membranes containing TRP channels
In this article we compare electrical conductance events from single channel
recordings of three TRP channel proteins (TRPA1, TRPM2 and TRPM8) expressed in
human embryonic kidney cells with channel events recorded on synthetic lipid
membranes close to melting transitions. Ion channels from the TRP family are
involved in a variety of sensory processes including thermo- and
mechano-reception. Synthetic lipid membranes close to phase transitions display
channel-like events that respond to stimuli related to changes in intensive
thermodynamic variables such as pressure and temperature. TRP channel activity
is characterized by typical patterns of current events dependent on the type of
protein expressed. Synthetic lipid bilayers show a wide spectrum of electrical
phenomena that are considered typical for the activity of protein ion channels.
We find unitary currents, burst behavior, flickering, multistep-conductances,
and spikes behavior in both preparations. Moreover, we report conductances and
lifetimes for lipid channels as described for protein channels. Non-linear and
asymmetric current-voltage relationships are seen in both systems. Without
further knowledge of the recording conditions, no easy decision can be made
whether short current traces originate from a channel protein or from a pure
lipid membraneComment: 13 pages, 9 Figure
Emergence of functional sensory subtypes as defined by transient receptor potential channel expression
The existence of heterogeneous populations of dorsal root ganglion (DRG) neurons conveying different somatosensory information is the basis for the perception of touch, temperature, and pain. A differential expression of transient receptor potential (TRP) cation channels contributes to this functional heterogeneity. However, little is known about the development of functionally diverse neuronal subpopulations. Here, we use calcium imaging of acutely dissociated mouse sensory neurons and quantitative reverse transcription PCR to show that TRP cation channels emerge in waves, with the diversification of functional groups starting at embryonic day 12.5 (E12.5) and extending well into the postnatal life. Functional responses of voltage-gated calcium channels were present in DRG neurons at E11.5 and reached adult levels by E14.5. Responses to capsaicin, menthol, and cinnamaldehyde were first seen at E12.5, E16.5, and postnatal day 0 (P0), when the mRNA for TRP cation channel, subfamily V, member 1 (TRPV1), TRP cation channel, subfamily M, member 8 (TRPM8), and TRP cation channel, subfamily A, member 1 (TRPA1), respectively, was first detected. Cold-sensitive neurons were present before the expression or functional responses of TRPM8 or TRPA1. Our data support a lineage relationship in which TRPM8- and TRPA1-expressing sensory neurons derive from the population of TRPV1-expressing neurons. The TRPA1 subpopulation of neurons emerges independently in two distinct classes of nociceptors: around birth in the peptidergic population and after P14 in the nonpeptidergic class. This indicates that neurons with similar receptive properties can be generated in different sublineages at different developmental stages. This study describes for the first time the emergence of functional subtypes of sensory neurons, providing new insight into the development of nociception and thermoreception
Lipid ion channels and the role of proteins
Synthetic lipid membranes in the absence of proteins can display quantized
conduction events for ions that are virtually indistinguishable from those of
protein channel. By indistinguishable we mean that one cannot decide based on
the current trace alone whether conductance events originate from a membrane,
which does or does not contain channel proteins. Additional evidence is
required to distinguish between the two cases, and it is not always certain
that such evidence can be provided. The phenomenological similarities are
striking and span a wide range of phenomena: The typical conductances are of
equal order and both lifetime distributions and current histograms are similar.
One finds conduction bursts, flickering, and multistep-conductance. Lipid
channels can be gated by voltage, and can be blocked by drugs. They respond to
changes in lateral membrane tension and temperature. Thus, they behave like
voltage-gated, temperature-gated and mechano-sensitive protein channels, or
like receptors. Lipid channels are remarkably under-appreciated. However, the
similarity between lipid and protein channels poses an eminent problem for the
interpretation of protein channel data. For instance, the Hodgkin-Huxley theory
for nerve pulse conduction requires a selective mechanism for the conduction of
sodium and potassium ions. To this end, the lipid membrane must act both as a
capacitor and as an insulator. Non-selective ion conductance by mechanisms
other than the gated protein-channels challenges the proposed mechanism for
pulse propagation. ... Some important questions arise: Are lipid and protein
channels similar due a common mechanism, or are these similarities fortuitous?
Is it possible that both phenomena are different aspects of the same
phenomenon? Are lipid and protein channels different at all? ... (abbreviated)Comment: 10 pages, 10 figures - accepted by 'Accounts of Chemical Research
Did Going North Give Us Migraine? An Evolutionary Approach on Understanding Latitudinal Differences in Migraine Epidemiology
This commentary discusses a recent publication by evolutionary biologists with strong implications for migraine experts. The Authors showed that a gene polymorphism associated with migraine gave our ancestors an evolutionary advantage when colonizing northern, and thus colder, territories. They then highlight that the prevalence of migraine may differ among countries because of climatic adaptation. These results may prove useful in planning both epidemiological and physiological studies in the field of migraine
Direct Gα q Gating Is the Sole Mechanism for TRPM8 Inhibition Caused by Bradykinin Receptor Activation
Activation of Gα q-coupled receptors by inflammatory mediators inhibits cold-sensing TRPM8 channels, aggravating pain and inflammation. Both Gα q and the downstream hydrolysis of phosphatidylinositol 4, 5-bisphosphate (PIP 2) inhibit TRPM8. Here, I demonstrate that direct Gα q gating is essential for both the basal cold sensitivity of TRPM8 and TRPM8 inhibition elicited by bradykinin in sensory neurons. The action of Gα q depends on binding to three arginine residues in the N terminus of TRPM8. Neutralization of these residues markedly increased sensitivity of the channel to agonist and membrane voltage and completely abolished TRPM8 inhibition by both Gα q and bradykinin while sparing the channel sensitivity to PIP 2. Interestingly, the bradykinin receptor B2R also binds to TRPM8, rendering TRPM8 insensitive to PIP 2 depletion. Furthermore, TRPM8-Gα q binding impaired Gα q coupling and signaling to PLCÎČ-PIP 2. The crosstalk in the TRPM8-Gα q-B2R complex thus determines Gα q gating rather than PIP 2 as a sole means of TRPM8 inhibition by bradykinin. TRPM8 channels are inhibited by receptors coupled to Gα q, contributing to pain and inflammation. Zhang reveals Gα q gating sites on TRPM8 and shows that bradykinin receptor solely uses Gα q gating sites for TRPM8 inhibition upon activation, while depriving the channel of sensitivity to PIP 2
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