Biomedical Engineering Reference
In-Depth Information
identi fi ed both G a and Gb g as direct interacting proteins of Kir3, forming the basis
of a macromolecular ion channel-GPCR signaling complex, although Kir2 channel
did not seem to show a similar association. Like L-type calcium channels, co-immu-
noprecipitation experiments confirmed that the assembly of G protein signaling
molecules, scaffolding proteins, cytoskeletal proteins, kinases (GRK, PKA) and
phosphatases (PP1, PP2a) was a prerequisite for G-protein regulation of GIRK
channels (Nikolov and Ivanova-Nikolova
2004
). Whether the GPCR-Kir3 channel
signaling complex involves a direct interaction between channel and receptor is an
open question. The Ga and Gb g, which interact with both channel and receptor and
induce channel gating, may contribute to the molecular organization of the com-
plex. Notably, heteromeric G proteins have been shown to form stable complexes
with adenylyl cyclase and the Kir3 channel (Lavine et al.
2002
; Rebois et al.
2006
) .
Additional regulatory proteins such as RGS (Regulators of G protein Signalling)
proteins may also play a scaffolding role via direct association with the Ga and the
receptor itself (Georgoussi et al.
2006
; Jaen and Doupnik
2006
; Abramow-Newerly
et al.
2006
). Evidence for association of the GABA
B
receptor with RGS4 and Kir3
channels was also confirmed (Fowler et al.
2007
). Given that RGS proteins are
capable of direct interaction with GPCRs, as exemplified by RGS2 and the M1
muscarinic receptors (Bernstein et al.
2004
), one may expect that the RGS protein
family plays both regulatory and chaperone roles to stabilize the signaling complex.
Finally, the membrane-associated guanylate kinase (MAGUK) protein family (i.e.,
SAP97, PSD95, and CASK), was recently shown to be involved in generating the
complex (Cohen et al.
1996
; Leonoudakis et al.
2001,
2004
) . These proteins are
well described scaffolding proteins that regulate the subcellular distribution of
several ligand-gated, voltage-gated channels and GPCRs, sometimes in an activity
dependent manner as thoroughly characterized for the NMDA glutamate receptor
(Gardoni
2008
). MAGUK proteins are able to directly interact with GPCRs, enhanc-
ing the repertoire of associated proteins forming the GPCR-GIRK channel complex
and likely contributing to its stabilization (Tilakaratne and Sexton
2005
) .
13.4
Conclusion
Ion channels and G protein-coupled receptors (GPCRs) are integral transmembrane
proteins that play fundamental physiological functions. The recent effort by many
groups to characterize these macromolecular signaling complexes between GPCRs
and ion channels has confirmed the importance of the functional relationship
between them. It is generally accepted that these proteins are localized in membrane
microdomains and organized in multi partner complexes which often contain scaf-
folding proteins as well as modifying enzymes such as kinases and phosphatases.
Lately, the notion of a direct physical linkage between GPCRs and ion channels has
emerged. These direct associations can regulate the activity of ion channels via
constitutive mechanisms, dependent (N-type channels) or independent of G protein
signaling (MaxiK channels). Finally, it was recently recognized that the physical
Search WWH ::
Custom Search