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Regulation of Ion Channels by Integrins Michael J © Copyright 2002 by Humana Press Inc. All rights of any nature whatsoever reserved. 1085-9195/02/36/41–66/$16.50 REVIEW ARTICLE Regulation of Ion Channels by Integrins Michael J. Davis,*,1 Xin Wu,1 Timothy R. Nurkiewicz,1 Junya Kawasaki,1 Peichun Gui,1 Michael A. Hill,2 and Emily Wilson1 1Department of Medical Physiology, Cardiovascular Research Institute, Texas A&M University System Health Science Center, College Station, TX; and 2Department of Human Biology, RMIT University, Bundoora, Victoria, Australia Abstract Ion channels are regulated by protein phosphorylation and dephosphorylation of serine, threo- nine, and tyrosine residues. Evidence for regulation of channels by tyrosine phosphorylation comes primarily from investigations of the effects of growth factors, which act through receptor tyrosine kinases. The purpose of the present work is to summarize evidence for the regulation of ion channels by integrins, through their downstream, nonreceptor tyrosine kinases. We review both direct and indirect evidence for this regulation, with particular emphasis on Ca2+-activated K+ and voltage-gated Ca2+ channels. We then discuss the critical roles that cytoskeletal, focal-adhe- sion, and channel-associated scaffolding proteins may play in localizing nonreceptor tyrosine kinases to the vicinity of ion channels. We conclude by speculating on the physiological signifi- cance of these regulatory pathways. Index Entries: Receptor tyrosine kinase; nonreceptor tyrosine kinase; integrins; cytoskeleton; focal adhesion; growth factor receptors; scaffolding proteins; Src; FAK; AKAP; SH3. INTRODUCTION properties, including voltage sensitivity and cal- cium sensitivity, and thereby dramatically con- Ion channels are the targets of many intra- trol the electrophysiological properties of a cell. cellular signaling pathways, including pro- In addition to serine/threonine phosphoryla- tein phosphorylation and dephosphorylation. tion, considerable recent evidence suggests that Indeed, nearly every type of voltage-gated K+, ion channels are also regulated by phosphoryla- Ca2+, and Na+ channel is regulated to some tion on tyrosine residues (1,3–7). extent by phosphorylation of serine/threonine Evidence for regulation of ion channels by residues on intracellular domains of the channel tyrosine phosphorylation comes primarily from (1,2). Phosphorylation can alter channel gating investigations of the effects of growth factors. Growth factors, which act through receptor * Author to whom all correspondence and reprint protein tyrosine kinases (PTKs), regulate the requests should be addressed. E-mail: [email protected] long-term expression of ion channels (8,9) but Cell Biochemistry and Biophysics 41 Volume 36, 2002 42 Davis et al. also have acute actions on channel activity. to some extent, previously (3,4,6,7). The pur- Receptor PTKs are characterized by an extracel- pose of the present work is to summarize evi- lular, ligand-binding domain, a transmembrane dence for the regulation of ion channels by domain, a kinase-catalytic domain and cyto- integrins and integrin-linked tyrosine kinases. plasmic regions responsible for coordinating We review both direct and indirect evidence for the subsequent activity of signaling molecules. this regulation. We then discuss the critical Signal transduction involves growth factor roles that the cytoskeleton and channel-associ- (ligand) binding to the extracellular domain, ated scaffolding proteins may play in localiz- dimerization of the receptor proteins, and ing PTKs to the vicinity of ion channels. When autophosphorylation of the receptor. Receptor possible, we speculate on the physiological sig- autophosphorylation then creates phosphory- nificance of these regulatory pathways. lated tyrosine residues on the cytoplasmic tail of the receptor, which form docking sites for INTERACTIONS BETWEEN signaling molecules. The combination of these signaling molecules determines the specificity INTEGRINS AND ION CHANNELS of individual receptor PTKs (10). Integrins are a family of membrane-span- Nonreceptor PTKs can also regulate ion chan- ning glycoproteins that link the extracellular nels. These enzymes play a prominent role in matrix (ECM) to the cytoskeleton. Integrins are signaling pathways downstream from integrins composed of α–β heterodimers with extracellu- and other adhesion molecules. Nonreceptor lar domains that bind ECM proteins and short PTKs are found in both the cytoplasm and cytoplasmic tails that associate with focal adhe- nuclei of cells, but the largest family is the cyto- sion proteins (14,15). As mentioned earlier, plasmic Src (sarcoma virus tyrosine kinase) fam- integrin activation is a well-known trigger of ily (11), consisting of eight members, including intracellular tyrosine phosphorylation cas- Src, Fyn, and Yes, that are ubiquitously cades. Integrin engagement by multivalent lig- expressed. Regulation of Src family members is ands, including extracellular matrix proteins, highly conserved: Autophosphorylation of a induces receptor clustering, the recruitment of kinase domain tyrosine leads to increased kinase cytoskeletal proteins to the focal adhesion, and activity, whereas phosphorylation of a tyrosine the activation of nonreceptor PTKs (16,17). residue near the C terminus represses activity Because integrins lack intrinsic enzymatic (12). Many stimuli, including receptor PTKs, G- activity, they rely on the activation of other protein coupled receptors, and integrins have cytoplasmic signaling molecules, including been implicated in Src activation, suggesting FAK and Src. Integrin interaction with FAK that this family of kinases is a key point of inte- leads to FAK autophosphorylation, to the cre- gration for many signal transduction pathways. ation of a binding site for the Src SH2 domain, Another relevant nonreceptor PTK is pp125FAK, and, ultimately, to Src activation (18). Src then which is discretely localized to cellular focal phosphorylates additional sites on FAK to adhesions and has been shown to colocalize allow binding of other signaling molecules and with integrins. FAK is a substrate for integrin- scaffolding proteins (19,20). This process leads dependent tyrosine phosphorylation and to the assembly of complex signaling mole- becomes enzymatically active upon phosphory- cules at the focal adhesion site and organizes lation, serving as a scaffold for the binding and further downstream signaling events (15). localization of other proteins to the focal adhe- Many of the signaling pathways activated by sion (13). Activation of Src family members and receptor PTKs overlap with integrin-mediated FAK serves as a key integration mechanism for a signaling pathways, utilizing the same PTKs number of extracellular signaling pathways. through different adaptor proteins (21,22). The regulation of ion channels by growth Integrins may play a role in directing the factors and receptor PTKs has been reviewed, localization of ion channels. In neuroblastoma Cell Biochemistry and Biophysics Volume 36, 2002 Regulation of Ion Channels by Integrins 43 cells, neurite outgrowth is initiated by hyperpo- In addition to a possible role in channel larization subsequent to β1-integrin-dependent localization, evidence from a large number of adhesion on extracellular matrix (23). G-pro- studies indicates that integrins play a func- tein-coupled inwardly rectifying K+ (GIRK) tional role in ion channel regulation. For exam- channels are implicated in this hyperpolariza- ple, integrin-dependent adhesion initiates Ca2+ tion, although the mechanism and possible cou- influx in endothelial cells (28,29), fibroblasts pling of these channels to β1 integrins has not (30), osteoclasts (31–33), leukocytes (34), hepa- been elucidated. In oocytes, GIRK1 and GIRK4 tocytes (35), smooth-muscle cells (36) and channels coimmunoprecipitate with an endoge- epithelial cells (37). Integrins are involved in nous β1-integrin subunit (24). The Asp-Gly-Arg the mechanical modulation of neurotransmit- (RGD) sequence is thought to be an integrin- ter release (38,39). Integrin-dependent adhe- specific recognition sequence contained in sion inititiates hyperpolarization in neurons many extracellular matrix proteins and this (23,40). Integrin-specific peptides (RGD, LDV) sequence is also found in the first membrane- cause vasodilation and vasoconstriction in iso- spanning (extracellular) region of all known lated skeletal muscle arterioles (41), responses GIRK channels, but not in any other cloned K+ that are blocked by inhibitors of K+ and Ca2+ channels (24). Interestingly, mutation of the channels, respectively (42). Integrin-mediated RGD site (to RGE) on the channel decreases or tyrosine phosphorylation cascades have been eliminates GIRK current after expression of the implicated in a number of processes that mutant channel. However, RGD peptides, involve ion channels (43). The majority of these applied extracellularly, do not modulate GIRK studies are summarized in Tables 1 and 2. channel current. This evidence suggests that the Relatively few studies have defined specific RGD site is important for insertion of the chan- interactions between an integrin and a channel. nel into the cell membrane, rather than for The exceptions are noted in Table 1. For the sake acute regulation of the channel (24). However, of brevity, we will discuss only a few selected only the aspartate residue, not the entire RGD studies. KCa channels in erythroleukemia cells motif, appears to be important for proper GIRK are activated following cell contact with processing and
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