The vagus nerve plays a role in mediating effects of the two glucagon-like peptides GLP-1 and GLP-2 on gastrointestinal growth, functions and eating behaviour. To obtain electrophysiological and molecular evidence for the contribution of afferent pathways in chemoreception from the gastrointestinal tract, afferent mass activity in the ventral gastric branch of the vagus nerve and gene expression of GLP-1 receptors and GLP-2 receptors in the nodose ganglion were examined in Sprague-Dawley rats. Intravenous administration of GLP-1 (30-1000 pmol kg(-1)), reaching high physiological plasma concentrations, increased vagal afferent mass activity peaking (13-52% above basal level, P < 0.05) 3-5 min after injection. Repeated administration of GLP-1 (1000 pmol kg(-1); five times, 15 min intervals) elicited similar responses. Pretreatment with GLP-1 receptor antagonist exendin(9-39)amide (500 pmol kg(-1)) abolished the GLP-1 response to doses 30-300 pmol kg(-1) but had no effect on the vagal response to gastric distension. For comparison, GLP-2 (1000 pmol kg(-1)) had no effect on vagal afferent activity. Vagal chemoreception of GLP-1 is supported by expression of the GLP-1 receptor gene in the nodose ganglion. However, the GLP-2 receptor was also expressed. To conclude, our results show that peripherally administered GLP-1, differently from GLP-2, activates vagal afferents, with no evidence of desensitisation. The GLP-1 effect was blocked by exendin(9-39)amide, suggesting that GLP-1 receptors on vagal afferent nerves mediate sensory input from the gastrointestinal tract or pancreas; either directly or indirectly via the release of another mediator. GLP-2 receptors appear not be functionally expressed on vagal afferents.

SUMMARY1. The membrane characteristics of the slowly adapting stretch receptor from the crayfish, Asta8us fiuviatilis, were examined with electrophysiological techniques consisting of membrane potential recording, voltage clamp and ion-sensitive microelectrodes.2. The passive membrane current (Ip) following step changes of the membrane potential to levels above 0 mV required more than a minute to decay to a steadystate level.3. The stretch-induced current (SIC, where SIC = total -Ipassive) was not fully developed until the Ip had decayed to a steady state.4. With Ip at the steady state and the stretch-induced current at the 0-current potential, a slow stretch-induced inward current was isolated. The latter reaches a maximum after 1 see of stretch and declines even more slowly after stretch. The I-V relation of the slow current had a negative slope and reversed sign near the resting potential. It is suggested that this current is due to a Cl-conductance change.5. The stretch-induced current, consisting of a rapid transient phase and a steady component can be isolated from the slow stretch-induced current at a holding potential corresponding to the resting potential.6. The SIC-Em relation is non-linear and reverses sign at about +15 mV.7. In a given cell, the reversal potential of the stretch-induced potential change obtained with current clamp coincided with the 0-current potential of the stretchinduced current obtained by voltage clamp. The average value from twenty-six cells was + 13 + 6'5 mV; cell to cell variability seemed to be correlated with dendrite length.8. Tris (mol. wt. 121) or arginine (mol. wt. 174) substituted for Na+ reduces but does not abolish the stretch-induced current.9. The permeability ratios of Tris: Na and arginine: Na were estimated from changes in the 0-current potential as these cations replaced Na+ in the eternal medium. The PTr, :PNa was somewhat higher (0-31) than the Parginine:PN ratio (0.25).10. Changes in the external Ca2+ concentration had no effect on the 0-current potential in Na or Tris saline. However, reducing Ca2+ did augment the stretchinduced current in either saline. A tenfold reduction of Ca2+ increased the conductance (at the 0-current level) about twofold.

1. A mathematical model of the primary transduction process in a mechanoreceptor, the slowly adapting stretch receptor organ of the crayfish, has been developed taking into account the viscoelastic properties of the accessory structures of the receptor, i.e., the receptor muscle, the biophysical properties of the mechanosensitive channels (MSCs) and the passive electrical properties of the neuronal membrane (leak conductance and capacitative properties). The work is part of an effort to identify and characterize the mechanical and ionic mechanisms in a complex mechanoreceptor. The parameters of the model are based mainly on results of our own experiments and to some extent on results from other studies. The performance of the model has been compared with the performance of the slowly adapting receptor. 2. The model resulted in nonlinear differential equations that were solved by an iterative, fourth order Range-Kutta method. For the calculations of potential, the cell was treated as an idealized spherical body. The extension of the receptor muscle was 0-30%, which is within the physiological limits for this receptor. 3. The mechanical properties of the receptor muscle were modeled by a simple Voigt element (a spring in parallel with a dashpot) in series with a nonlinear spring. This element can describe resonably well the tension development in the receptor muscle at least for large extensions (> 12%). However, for small extensions (< 12%), the muscle seems to be more stiff than for large extensions. 4. The receptor current at different extensions of the receptor was computed using typical viscoelastic parameters for a receptor muscle together with a transformation of muscle tension to tension in the neuronal dendrites and finally the properties of the mechanosensitive channels. The model fit was satisfactory in the high extension range whereas in the low extension range the deviation from the experimental results could be explained partly by insufficient modeling of the nonlinear viscoelastic properties. The voltage dependence of the receptor current was also well predicted by the model. 5. If the parameters of the viscoelastic model were adjusted for each extension so that each tension response closely resembled the experimental values, the fit of the current responses was improved but still deviated from the experimental currents. One factor that might explain the difference is the possibility that the MSCs in the stretch receptor neuron might have intrinsic adaptive properties. Introducing an exponential adaptive behavior of individual MSCs increased the ability of the model to predict the receptor current. 6. The receptor potential was calculated by modeling the neuronal membrane by a lumped leak conductance and capacitance The calculated receptor potential was higher than the experimental receptor potential. However, the fit of the receptor potential was improved substantially by introducing an adaptation of the MSCs as outlined in the preceding paragraph. the remaining discrepancy might be explained by ins...

The receptor potential and receptor current in response to ramp-and-hold extensions were measured in the slowly adapting stretch receptor of the crayfish, using potential clamp technique. The stimulus-response relationship for the peak amplitude of the receptor current showed a linear behaviour for extensions less than 2% and a nonlinear behaviour for extensions larger than 5%. Using the Stevens power law, R = k(S--S0)n, where R is response, S is stimulus, S0 is threshold stimulus and n the power coefficient, n was found to be 3 for extensions between 5 and 15%. The receptor current saturated at extensions above 20-25% of the zero length of the muscle, resulting in a lower n value. However, the n value is difficult to define in this region due to the saturation. The stimulus-response relation for the receptor current can be explained by the properties of the stretch-activated channels for which the open probability is exponentially dependent on the square of the membrane tension, as suggested by recent findings. The receptor potential, using tetrodotoxin, in response to identical ramp-and-hold extensions as those used to record current responses showed a more complex time-course, indicating involvement of potential-dependent channels, potassium channels being the most probable candidate. This was supported by a mathematical model which takes into account the viscoelastic properties of the receptor muscle, the properties of the stretch-activated channels and a potential dependent K+ current.

SUMMARY1. The transducer properties of the rapidly adapting stretch receptor neurone of the crayfish (Pacifastacus leniusculus) were studied using a two-microelectrode voltage clamp technique.2. The impulse response to ramp-and-hold extensions of the receptor muscle typically consisted of a high frequency burst followed by cessation of impulses within a relatively short time depending on the amplitude of extension. The type of adaptation was consistent with earlier studies. The stimulus-response relationship for the impulse frequency was non-linear and had a slope in a log-log plot of 2-9.3. When impulse generation was blocked by tetrodotoxin (TTX), (block of Na+ channels) the receptor potential was extension dependent and similar to that found in the slowly adapting receptor. For small extensions there was an initial peak followed by a fall to a steady potential level. For large extensions the potential response during the ramp phase consisted of a peak followed by a constant potential level lasting to the end of the ramp. When the extension changed to the hold phase the potential fell towards a steady state. The relation between extension and amplitude of receptor potential was non-linear and saturated at -40 to -30 mV (extensions > 15% of zero length, lo).4. When potassium channels were blocked by TEA (50 mM) and 4-aminopyridine (4-AP, 5 mm) (and Na+ channels blocked by TTX) the shape of the generator potential become less complex with an increased amplitude for large extensions.5. When the receptor neurone was voltage clamped at the resting potential, extension of the receptor muscle produced an inwardly directed receptor current, the stretch-induced current (SIC). The response consisted of a fast transient phase which decayed towards a steady state. The SIC peak amplitude was dependent on extension in a sigmoidal fashion and saturated at 190 nA (extensions > 25 % of lo). The slope of the steepest part of the stimulus-response relation (between 10 and 20 % extension) was 4-7 + 0-25 (mean + s.E.M.) in a log-log plot.6. The peak amplitude of the SIC increased with increasing extension speed (ramp steepness), the relation between the slope of the ramp and current amplitude being a first order (hyperbolic) function. The amplitude of the receptor current was voltage dependent and had a reversal potential of + 16-2 + 1-8 mV (mean +S.E.M., 32 cells). MS 1767 B. RYDQVIST AND N. PURALIFrom the reversal potential the permeability ratio, PNa/PK, of the transducer permeability system was calculated to be 1P5. The I-V curve of SIC was non-linear.7. When the external Ca2+ concentration was lowered the receptor current amplitude increased. This led to displacement of the stimulus-response relation towards smaller extensions. No change in reversal potential was observed.8. The receptor current amplitude was reduced when the normal bathing solution was replaced by solutions containing mainly Ca2+ or Mg2+ ions. Small changes in the reversal potential for the receptor current were seen. Calculations from the current amplitudes...