G protein coupling of receptors to ionic channels and other effector systems.

Abstract

1. Four questions raised by previous studies that had shown activation of K+ channels by alpha subunits of the type 3 Gi protein are addressed in the present communication: a) are K+ channels specific for one Gi? b) are there more ionic channels under direct G protein control? c) can we confirm using recombinant G alpha s the results obtained with biochemically resolved G alpha s and continue ascribing the regulatory effector to this part of the alpha beta gamma holo‐G protein? and d) can we confirm that a single G alpha, Gs alpha in this case, is able to affect more than one type of effector function? 2. We found Gi alpha s are isoforms, that there exist also Gi‐insensitive, Go‐responsive K+ channels and that G alpha s can be multifunctional. Thus, a single receptor will elicit cellular responses that will depend on the endogenous G protein as well as the type of effector function expressed in it. 3. In another set of experiments we found that G beta gamma s, be they derived from human erythrocytes, human placenta, bovine brain or bovine retina, all inhibit Gk‐gated K+ channel activity as seen in inside out membrane patches with GTP as the driving nucleotide. In addition we noted that inhibition was much more effective under basal (no agonist in the pipette) than agonist stimulated conditions, as reported in earlier experiments in which beta‐adrenoceptors, Gs and catalytic unit of adenylyl cyclase had been incorporated into phospholipid vesicles. 4. We propose that one of the roles of G beta gamma s in membranes is to quench ligand independent G protein activation by unoccupied receptors. Other roles of G beta gamma s are: a) by re‐associating with GDP‐G alpha s, to promote interaction with receptors, and b) by dissociating from activated R.G alpha *GTP.beta gamma, to allow for receptor dissociation from GTP‐activated G alpha s, which is required to satisfy the catalytic mode of receptor action.

Emerging paradigms of β-arrestin-dependent seven transmembrane receptor signaling

“…adenylate cyclase and phospholipases) and ion channels to generate second messengers (e.g. cAMP) and initiate appropriate signaling responses [6]. As one activated receptor can sequentially couple to multiple G proteins, cells have devised desensitization mechanisms to turn off G protein-dependent signaling in order to avoid the deleterious effects of sustained signaling [8].…”

Theoretical Aspects of GPCR–Ligand Complex Pharmacology

“…7TMR receptor models as various parts of the thermodynamically complete cubic ternary complex model: classical model, ,,,− simple two-state model, − simple ternary complex model, − full two-state model, ,− ternary complex model, − extended ternary complex model, , cubic ternary complex model. − …”

Morphine decreases the voltage sensitivity of slow sodium channels

“…Activation or inhibition of G-proteins, which link opioid receptors with their effector systems, can have significant effects on the affinity of this agonist to the receptor. An important property of G-proteins, allowing their roles in intracellular signaling processes to be studied effectively, is the fact that they can be irreversibly activated or inactivated by the non-hydrolyzable GTP analog guanosine-5'-O-(3-thiophosphate) (GTP~S) and guanosine-5'-O-(2-thiodiphosphate) (GDPI~S) respectively [7]. The use of activators and inhibitors of G-proteins without morphine produced no changes in the effective charge in our experiments.…”