30
3
What You Will Learn in This Chapter
G-protein coupled receptors (GPCRs) are integral membrane proteins that span the membrane seven times. They are coupled to trimeric G-proteins. In this chapter we will discuss
the history of their discovery, introduce the concept of second messengers and specifically
explain how second messengers arise in response to GPCR-signalling. We will focus on
cAMP and phospholipids. Finally we will introduce target enzymes for these second messengers including protein kinase A and protein kinase C.
3.1 G-Protein-Coupled Receptors
G-protein-coupled receptors are integral membrane proteins that span the plasma membrane seven times. Due to this characteristic, they are also called “seven-transmembrane
receptors” or serpentine receptors (see . Fig. 3.1).
In nematodes, over 1000 genes are dedicated to express GPCRs. This number adds up
to 5.5% of the Caenorhabditis elegans genome. Many of these GPCRs have no known
ligand, making them so-called “orphan” receptors. By contrast, in the yeast Saccharomyces
cerevisiae, only three genes encoding GPCRs are known. These include STE 2 and STE 3,
two pheromone receptors important for mating. In plants, such receptors are also rare,
and the few serpentine receptors encoded in the plant genomes are not G-protein-coupled
(Fredriksson and Schioth 2005).
In humans about 800 genes for GPCRs have been annotated (Civelli 2012). Thus,
GPCRs constitute the largest group of membrane proteins encoded in the human genome,
and they are targets for the majority of present-day therapeutic drugs. About 400 GPCRs
in vertebrates are olfactory receptors dedicated to sensing smell and taste. In most cases
the endogenous ligands of olfactory receptors are not known (Tao and Conn 2014). Nonolfactory GPCRs include, to name just a few, rhodopsin in our photoreceptors, adrenergic
receptors, acetylcholine receptors, dopamine and serotonin receptors and peptide receptors, e.g. such for opiate peptides and blood pressure regulators like angiotensin and bradykinin. Cannabinoid receptors fall into this molecule class, as do adenosine receptors
that are antagonized by caffeine. A recent review states about 360 well-characterized
GPCRs with 200 endogenous ligands, whereas 160 of non-olfactory receptors are still
“orphans” (Civelli 2012).
Functionally related to the animal GPCRs are light-driven proton pumps that were
discovered by Oesterhelt and Stoeckenius in the purple membrane of Halobacterium salinarum in 1971 (Oesterhelt and Stoeckenius 1971). Henderson and Unwin described their
structure in 1975 as a “simple example of an intrinsic membrane protein” (Henderson and
Unwin 1975). Retinal binds to these proton pumps, and, as a prosthetic group, it mediates
the establishment of a proton gradient across the membrane of Halobacterium salinarum.
Upon light absorption, retinal isomerizes from all-trans to 13-cis-retinal, and protons
move to the exterior (Oesterhelt and Stoeckenius 1971). Halobacteria, in addition to the
proton pumps, also express a chloride pump and two types of sensory rhodopsins that
mediate chemotaxis. On the sequence level, these archaeal rhodopsin family members are
not related to eukaryotic GPCRs (Ihara et al. 1999). However, their function pre-empts the
use of proton gradients in eukaryotic ATPases and the use of retinal as a prosthetic group
in animal photoreceptors. Retinal is the aldehyde of retinol, and animals synthesize it
from β-carotene (or provitamin A), which is found in carrots and in many other roots,
fruits and leaves of plants. It is also the prosthetic group for the animal opsins. With retinal
Chapter 3 · GPCRs
3
What You Will Learn in This Chapter
G-protein coupled receptors (GPCRs) are integral membrane proteins that span the membrane seven times. They are coupled to trimeric G-proteins. In this chapter we will discuss
the history of their discovery, introduce the concept of second messengers and specifically
explain how second messengers arise in response to GPCR-signalling. We will focus on
cAMP and phospholipids. Finally we will introduce target enzymes for these second messengers including protein kinase A and protein kinase C.
3.1 G-Protein-Coupled Receptors
G-protein-coupled receptors are integral membrane proteins that span the plasma membrane seven times. Due to this characteristic, they are also called “seven-transmembrane
receptors” or serpentine receptors (see . Fig. 3.1).
In nematodes, over 1000 genes are dedicated to express GPCRs. This number adds up
to 5.5% of the Caenorhabditis elegans genome. Many of these GPCRs have no known
ligand, making them so-called “orphan” receptors. By contrast, in the yeast Saccharomyces
cerevisiae, only three genes encoding GPCRs are known. These include STE 2 and STE 3,
two pheromone receptors important for mating. In plants, such receptors are also rare,
and the few serpentine receptors encoded in the plant genomes are not G-protein-coupled
(Fredriksson and Schioth 2005).
In humans about 800 genes for GPCRs have been annotated (Civelli 2012). Thus,
GPCRs constitute the largest group of membrane proteins encoded in the human genome,
and they are targets for the majority of present-day therapeutic drugs. About 400 GPCRs
in vertebrates are olfactory receptors dedicated to sensing smell and taste. In most cases
the endogenous ligands of olfactory receptors are not known (Tao and Conn 2014). Nonolfactory GPCRs include, to name just a few, rhodopsin in our photoreceptors, adrenergic
receptors, acetylcholine receptors, dopamine and serotonin receptors and peptide receptors, e.g. such for opiate peptides and blood pressure regulators like angiotensin and bradykinin. Cannabinoid receptors fall into this molecule class, as do adenosine receptors
that are antagonized by caffeine. A recent review states about 360 well-characterized
GPCRs with 200 endogenous ligands, whereas 160 of non-olfactory receptors are still
“orphans” (Civelli 2012).
Functionally related to the animal GPCRs are light-driven proton pumps that were
discovered by Oesterhelt and Stoeckenius in the purple membrane of Halobacterium salinarum in 1971 (Oesterhelt and Stoeckenius 1971). Henderson and Unwin described their
structure in 1975 as a “simple example of an intrinsic membrane protein” (Henderson and
Unwin 1975). Retinal binds to these proton pumps, and, as a prosthetic group, it mediates
the establishment of a proton gradient across the membrane of Halobacterium salinarum.
Upon light absorption, retinal isomerizes from all-trans to 13-cis-retinal, and protons
move to the exterior (Oesterhelt and Stoeckenius 1971). Halobacteria, in addition to the
proton pumps, also express a chloride pump and two types of sensory rhodopsins that
mediate chemotaxis. On the sequence level, these archaeal rhodopsin family members are
not related to eukaryotic GPCRs (Ihara et al. 1999). However, their function pre-empts the
use of proton gradients in eukaryotic ATPases and the use of retinal as a prosthetic group
in animal photoreceptors. Retinal is the aldehyde of retinol, and animals synthesize it
from β-carotene (or provitamin A), which is found in carrots and in many other roots,
fruits and leaves of plants. It is also the prosthetic group for the animal opsins. With retinal
Chapter 3 · GPCRs