Susan F. Law

Molecular Mechanisms of Opiate Receptor Coupling to G Proteins and Effector Systemsa

Opiates are used extensively for the treatment of pain. They are the most effective analgesic agents available.2 The alkaloid opiates, such as morphine, and the endogenous opiate peptide transmitters, such as the enkephalins, induce their biological actions by interacting with three receptors, the mu, delta, and kappa receptor^.^.^ A number of opiates bind to these receptors with high affinity. However, each is characterized by its own pharmacology, which consists of highly selective agonists and antagonist^.^-^ Furthermore, the endogenous peptide transmitters show preferential interaction with these receptors, with enkephalins and endorphins binding with high affinity to the delta and mu receptors, and dynorphin A and its analogues binding selectively to kappa receptors. They share approximately 65 -70% amino acid sequence similarity, primarily in their transmembrane spanning regions and intracellular loops. Regions that diverge in amino acid sequence are the N and C termini, transmembrane four, and the second and third extracellular loops.I These regions may be important for functional differences of the receptors, such as their selectivities for particular ligands and their differential sensitivity to agonistinduced regulation. The three cloned receptors have been expressed in cell lines, and their pharmacological characteristics have been tested.16 The ligand selectivities of the mu and kappa receptors are similar to those reported for the mul and kappal receptors. The properties of the delta receptor are similar to those reported for the delta2 receptor subtype. The three opiate receptors have recently been

Somatostatin receptor activation of cellular effector systems.

Somatostatin (SRIF) induces its multiple biological actions by interacting with a family of receptors, referred to as SSTR1-SSTR5. These receptors are capable of associating with particular guanine nucleotide binding proteins to couple the receptors to distinct cellular effector systems. Therefore, G proteins have an important role in directing SRIF signalling and may provide the molecular basis for the diverse cellular actions of SRIF.

14 – Purification of Somatostatin Receptors

Publisher Summary This chapter presents the experimental results of studies carried out to test purification of somatostatin receptors. The neuropeptide somatostatin (SRIF) is expressed in the central nervous system, and in endocrine and exocrine organs. In the brain, SRIF is a neurotransmitter that regulates neuronal activity and the release of other transmitters, and it may be involved in the generation of centrally mediated behaviors such as movement and cognition. SRIF released from neurons in the hypothalamus acts as a neurohormone in the pituitary and is the major physiological regulator of growth hormone secretion. A procedure to purify brain SRIF receptors to near homogeneity through the use of mild detergents and a SRIF affinity column is developed. The yield of purified receptor is generally low as the affinity column only binds receptors with high affinity for SRIF. This indicates that only SRIF receptors coupled with G proteins bind to the affinity column. Most receptors are uncoupled from the G proteins either because of the solubilization procedure or for other unknown reasons.