Ganong's Review of Medical Physiology, 23rd Edition

54 SECTION ICellular & Molecular Basis of Medical Physiology

GTPase activity of the α subunit then converts GTP to GDP,
and this leads to reassociation of the α with the βγ subunit and
termination of effector activation. The GTPase activity of the
α subunit can be accelerated by a family of regulators of G
protein signaling (RGS).
Heterotrimeric G proteins relay signals from over 1000
GPCRs, and their effectors in the cells include ion channels
and enzymes (Table 2–5). There are 20 α, 6 β, and 12 γ genes,
which allow for over 1400 α, β, and γ combinations. Not all
combinations occur in the cell, but over 20 different heterotri-
meric G proteins have been well documented in cell signaling.
They can be divided into five families, each with a relatively
characteristic set of effectors.

G PROTEIN-COUPLED RECEPTORS

All the heterotrimeric G protein-coupled receptors (GPCRs)
that have been characterized to date are proteins that span the
cell membrane seven times. Because of this structure they are
alternatively referred to as seven-helix receptors or serpen-
tine receptors. A very large number have been cloned, and
their functions are multiple and diverse. The topological
structures of two of them are shown in Figure 2–24. These re-
ceptors further assemble into a barrel-like structure. Upon
ligand binding, a conformational change activates a resting
heterotrimeric G protein associated with the cytoplasmic leaf
of the plasma membrane. Activation of a single receptor can
result in 1, 10, or more active heterotrimeric G proteins, pro-
viding amplification as well as transduction of the first mes-
senger. Bound receptors can be inactivated to limit the
amount of cellular signaling. This frequently occurs through
phosphorylation of the cytoplasmic side of the receptor.

INOSITOL TRISPHOSPHATE

& DIACYLGLYCEROL AS

SECOND MESSENGERS

The link between membrane binding of a ligand that acts via

Ca2+ and the prompt increase in the cytoplasmic Ca2+ con-

centration is often inositol trisphosphate (inositol 1,4,5-tris-

phosphate; IP 3 ). When one of these ligands binds to its

receptor, activation of the receptor produces activation of

phospholipase C (PLC) on the inner surface of the membrane.

Ligands bound to G protein-coupled receptor can do this

through the Gq heterotrimeric G proteins, while ligands

bound to tyrosine kinase receptors can do this through other

cell signaling pathways. PLC has at least eight isoforms; PLCβ

FIGURE 2–23 Heterotrimeric G proteins. Top Summary of
overall reaction that occurs in the Gα subunit. Bottom: When the
ligand (square) binds to the G protein-coupled receptor in the cell
membrane, GTP replaces GDP on the α subunit. GTP-α separates from
the βγ subunit and GTP-α and βγ both activate various effectors, pro-
ducing physiologic effects. The intrinsic GTPase activity of GTP-α then
converts GTP to GDP, and the α, β, and γ subunits reassociate.

Nucleotide

exchange

Input GDP GTP

GTPase

activity

Output

Effectors

β

α γ

β

γ α

TABLE 2–5 Some of the ligands for receptors

coupled to heterotrimeric G proteins.

Class Ligand

Neurotransmitters Epinephrine

Norepinephrine

Dopamine

5-Hydroxytryptamine

Histamine

Acetylcholine

Adenosine

Opioids

Tachykinins Substance P

Neurokinin A

Neuropeptide K

Other peptides Angiotensin II

Arginine vasopressin

Oxytocin

VIP, GRP, TRH, PTH

Glycoprotein hormones TSH, FSH, LH, hCG

Arachidonic acid derivatives Thromboxane A 2

Other Odorants

Tastants

Endothelins

Platelet-activating factor

Cannabinoids

Light