Muscarinic ACh receptor-mediated control of thalamic activity via G(q)/G (11)-family G-proteins.
A genetic knock out was used to determine the specific contribution of G(q)/G(11)-family G-proteins to the function of thalamocortical relay (TC) neurons. Disruption of Galpha(q) function in a conditional forebrain-specific Galpha(q)/Galpha(11)-double-deficient mouse line (Galpha(q)/Galpha(11)(-/-) had no effects on the resting membrane potential (V (rest)) and the amplitude of the standing outward current (I (SO)). Stimulation of muscarinic acetylcholine (ACh) receptors (mAChR; muscarine, 50 microM) induced a decrease in I (SO) amplitude in wild-type mice (36 +/- 4%, n = 5), a constitutive Galpha(11)-deficient mouse line (Galpha(11)(-/-; 36 +/- 3%, n = 8), and Galpha(q)/Galpha(11)(-/-) (11 +/- 2%, n = 16). Current-clamp recordings revealed a muscarine-induced positive shift in V (rest) of 23 +/- 2 mV (n = 6), 18 +/- 5 mV (n = 5), and 2 +/- 1 mV (n = 9) in wild type, Galpha(11)(-/-), and Galpha(q)/Galpha(11)(-/-), respectively. This depolarization was associated with a change in TC neuron activity from burst to tonic firing in wild type and Galpha(11)(-/-), but not in Galpha(q)/Galpha(11)(-/-). The use of specific antibodies and of pharmacological agents with preferred affinity points to the contribution of m(1)AChR and m(3)AChR. In conclusion, we present two novel aspects of the physiology of the thalamocortical system by demonstrating that the depolarization of TC neurons, which is induced by the action of transmitters of ascending brainstem fibers, is governed roughly equally by both m(1)AChR and m(3)AChR and is transduced by Galpha(q) but not by Galpha(11).
Broicher
Tilman
T
Institut für Physiologie I, Westfälische Wilhelms-Universität Münster, Robert-Koch-Str. 27a, 48149, Münster, Germany.
Wettschureck
Nina
N
Munsch
Thomas
T
Coulon
Philippe
P
Meuth
Sven G
SG
Kanyshkova
Tatyana
T
Seidenbecher
Thomas
T
Offermanns
Stefan
S
Pape
Hans-Christian
HC
Budde
Thomas
T
D000818:Animals; D015153:Blotting, Western; D017931:DNA Primers / Q000737:chemistry; D004594:Electrophysiology; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000235:genetics / Q000378:metabolism*; D007150:Immunohistochemistry; D019426:Integrases / Q000378:metabolism / Q000502:physiology; D007763:Lac Operon / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018721:Muscarinic Agonists / Q000494:pharmacology; D009474:Neurons / Q000502:physiology; D018408:Patch-Clamp Techniques; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013788:Thalamus / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*
D017931:DNA Primers; D018721:Muscarinic Agonists; D011976:Receptors, Muscarinic; C045073:Cre recombinase; D019426:Integrases; D043802:GTP-Binding Protein alpha Subunits, Gq-G11